Trends in Application of SERS Substrates beyond Ag and Au, and Their Role in Bioanalysis.

This article compares the applications of traditional gold and silver-based SERS substrates and less conventional (Pd/Pt, Cu, Al, Si-based) SERS substrates, focusing on sensing, biosensing, and clinical analysis. In recent decades plethora of new biosensing and clinical SERS applications have fueled the search for more cost-effective, scalable, and stable substrates since traditional gold and silver-based substrates are quite expensive, prone to corrosion, contamination and non-specific binding, particularly by S-containing compounds. Following that, we briefly described our experimental experience with Si and Al-based SERS substrates and systematically analyzed the literature on SERS on substrate materials such as Pd/Pt, Cu, Al, and Si. We tabulated and discussed figures of merit such as enhancement factor (EF) and limit of detection (LOD) from analytical applications of these substrates. The results of the comparison showed that Pd/Pt substrates are not practical due to their high cost; Cu-based substrates are less stable and produce lower signal enhancement. Si and Al-based substrates showed promising results, particularly in combination with gold and silver nanostructures since they could produce comparable EFs and LODs as conventional substrates. In addition, their stability and relatively low cost make them viable alternatives for gold and silver-based substrates. Finally, this review highlighted and compared the clinical performance of non-traditional SERS substrates and traditional gold and silver SERS substrates. We discovered that if we take the average sensitivity, specificity, and accuracy of clinical SERS assays reported in the literature, those parameters, particularly accuracy (93-94%), are similar for SERS bioassays on AgNP@Al, Si-based, Au-based, and Ag-based substrates. We hope that this review will encourage research into SERS biosensing on aluminum, silicon, and some other substrates. These Al and Si based substrates may respond efficiently to the major challenges to the SERS practical application. For instance, they may be not only less expensive, e.g., Al foil, but also in some cases more selective and sometimes more reproducible, when compared to gold-only or silver-only based SERS substrates. Overall, it may result in a greater diversity of applicable SERS substrates, allowing for better optimization and selection of the SERS substrate for a specific sensing/biosensing or clinical application.

Ultrafast Nucleic Acid Detection Equipment with Silicon-Based Microfluidic Chip.

Recently, infectious diseases, such as COVID-19, monkeypox, and Ebola, are plaguing human beings. Rapid and accurate diagnosis methods are required to preclude the spread of diseases. In this paper, an ultrafast polymerase chain reaction (PCR) equipment is designed to detect virus. The equipment consists of a silicon-based PCR chip, a thermocycling module, an optical detection module, and a control module. Silicon-based chip, with its thermal and fluid design, is used to improve detection efficiency. A thermoelectric cooler (TEC), together with a computer-controlled proportional-integral-derivative (PID) controller, is applied to accelerate the thermal cycle. A maximum of four samples can be tested simultaneously on the chip. Two kinds of fluorescent molecules can be detected by optical detection module. The equipment can detect viruses with 40 PCR amplification cycles in 5 min. The equipment is portable, easily operated, and low equipment cost, which shows great potential in epidemic prevention.

Molecular detection of SARS-COV-2 in exhaled breath at the point-of-need.

The SARS-CoV-2 pandemic has highlighted the need for improved technologies to help control the spread of contagious pathogens. While rapid point-of-need testing plays a key role in strategies to rapidly identify and isolate infectious patients, current test approaches have significant shortcomings related to assay limitations and sample type. Direct quantification of viral shedding in exhaled particles may offer a better rapid testing approach, since SARS-CoV-2 is believed to spread mainly by aerosols. It assesses contagiousness directly, the sample is easy and comfortable to obtain, sampling can be standardized, and the limited sample volume lends itself to a fast and sensitive analysis. In view of these benefits, we developed and tested an approach where exhaled particles are efficiently sampled using inertial impaction in a micromachined silicon chip, followed by an RT-qPCR molecular assay to detect SARS-CoV-2 shedding. Our portable, silicon impactor allowed for the efficient capture (>85%) of respiratory particles down to 300 nm without the need for additional equipment. We demonstrate using both conventional off-chip and in-situ PCR directly on the silicon chip that sampling subjects' breath in less than a minute yields sufficient viral RNA to detect infections as early as standard sampling methods. A longitudinal study revealed clear differences in the temporal dynamics of viral load for nasopharyngeal swab, saliva, breath, and antigen tests. Overall, after an infection, the breath-based test remains positive during the first week but is the first to consistently report a negative result, putatively signalling the end of contagiousness and further emphasizing the potential of this tool to help manage the spread of airborne respiratory infections.

Ultrasensitive Detection of Interleukin 6 by Using Silicon Nanowire Field-Effect Transistors.

Interleukin 6 (IL-6) has been regarded as a biomarker that can be applied as a predictor for the severity of COVID-19-infected patients. The IL-6 level also correlates well with respiratory dysfunction and mortality risk. In this work, three silanization approaches and two types of biorecognition elements were used on the silicon nanowire field-effect transistors (SiNW-FETs) to investigate and compare the sensing performance on the detection of IL-6. Experimental data revealed that the mixed-SAMs-modified silica surface could have superior surface morphology to APTES-modified and APS-modified silica surfaces. According to the data on detecting various concentrations of IL-6, the detection range of the aptamer-functionalized SiNW-FET was broader than that of the antibody-functionalized SiNW-FET. In addition, the lowest concentration of valid detection for the aptamer-functionalized SiNW-FET was 2.1 pg/mL, two orders of magnitude lower than the antibody-functionalized SiNW-FET. The detection range of the aptamer-functionalized SiNW-FET covered the concentration of IL-6, which could be used to predict fatal outcomes of COVID-19. The detection results in the buffer showed that the anti-IL-6 aptamer could produce better detection results on the SiNW-FETs, indicating its great opportunity in applications for sensing clinical samples.

A Miniaturized Silicon Lab-on-Chip for Integrated PCR and Hybridization Microarray for High Multiplexing Nucleic Acids Analysis.

A silicon lab-on-chip, for the detection of nucleic acids through the integrated PCR and hybridization microarray, was developed. The silicon lab-on-chip manufactured through bio-MEMS technology is composed of two PCR microreactors (each volume 11.2 µL) and a microarray-hybridization microchamber (volume 30 µL), fluidically connected by buried bypass. It contains heaters and temperature sensors for the management and control of the temperature cycles during the PCR amplification and hybridization processes. A post-silicon process based on (i) plasmo-O2 cleaning/activation, (ii) vapor phase epoxy silanization, (iii) microarray fabrication and (iv) a protein-based passivation step was developed and fully characterized. The ssDNA microarray (4 rows × 10 columns) composed of 400 spots (spot size-70 ± 12 µm; spot-to-spot distance-130 ± 13 µm) was manufactured by piezo-dispense technology. A DNA microarray probe density in the range of 1310 to 2070 probe µm-2 was observed, together with a limit of detection of about 19 target µm-2. The performances of the silicon lab-on-chip were validated by the detection of the beta-globin gene directly from human blood. Remarkable sensitivity, multiplexing analysis and specificity were demonstrated for the detection of beta-globin and mycobacterium tuberculosis sequences.

A modified porous silicon microparticle potentiates protective systemic and mucosal immunity for SARS-CoV-2 subunit vaccine.

Development of optimal SARS-CoV-2 vaccines to induce potent, long-lasting immunity and provide cross-reactive protection against emerging variants remains a high priority. Here, we report that a modified porous silicon microparticle (mPSM) adjuvant to SARS-CoV-2 receptor-binding domain (RBD) vaccine activated dendritic cells and generated more potent and durable systemic humoral and type 1 helper T (Th) cell- mediated immune responses than alum-formulated RBD following parenteral vaccination, and protected mice from SARS-CoV-2 and Beta variant challenge. Notably, mPSM facilitated the uptake of SARS-CoV-2 RBD antigens by nasal and airway epithelial cells. Parenteral and intranasal prime and boost vaccinations with mPSM-RBD elicited stronger lung resident T and B cells and IgA responses compared to parenteral vaccination alone, which led to markedly diminished viral loads and inflammation in the lung following SARS-CoV-2 Delta variant challenge. Overall, our results suggest that mPSM is effective adjuvant for SARS-CoV-2 subunit vaccine in both systemic and mucosal vaccinations.

Directly immersible silicon photonic probes: Application to rapid SARS-CoV-2 serological testing.

Silicon photonic probes based on broad-band Mach-Zehnder interferometry are explored for the first time as directly immersible immunosensors alleviating the need for microfluidics and pumps. Each probe includes two U-shaped waveguides allowing light in- and out-coupling from the same chip side through a bifurcated fiber and a mechanical coupler. At the opposite chip side, two Mach-Zehnder interferometers (MZI) are located enabling real-time monitoring of binding reactions by immersion of this chip side into a sample. The sensing arm windows of the two MZIs have different length resulting in two distinct peaks in the Fourier domain, the phase shift of which can be monitored independently through Fast Fourier Transform of the output spectrum. The photonic probes analytical potential was demonstrated through detection of antibodies against SARS-CoV-2 in human serum samples. For this, one MZI was functionalized with the Receptor Binding Domain (RBD) of SARS-CoV-2 Spike 1 protein, and the other with bovine serum albumin to serve as reference. The biofunctionalized probes were immersed for 10 min in human serum sample and then for 5 min in goat anti-human IgG Fc specific antibody solution. Using a humanized rat antibody against SARS-CoV-2 RBD, a detection limit of 20 ng/mL was determined. Analysis of human serum samples indicated that the proposed sensor discriminated completely non-infected/non-vaccinated from vaccinated individuals, and the antibodies levels determined correlated well with those determined in the same samples by ELISA. These results demonstrated the potential of the proposed sensor to serve as an efficient tool for expeditious point-of-care testing.

An ASIP for Neural Network Inference on Embedded Devices with 99% PE Utilization and 100% Memory Hidden under Low Silicon Cost.

The computation efficiency and flexibility of the accelerator hinder deep neural network (DNN) implementation in embedded applications. Although there are many publications on deep neural network (DNN) processors, there is still much room for deep optimization to further improve results. Multiple dimensions must be simultaneously considered when designing a DNN processor to reach the performance limit of the architecture, including architecture decision, flexibility, energy efficiency, and silicon cost minimization. Flexibility is defined as the ability to support as many multiple networks as possible and to easily adjust the scale. For energy efficiency, there are huge opportunities for power efficiency optimization, which involves access minimization and memory latency minimization based on on-chip memory minimization. Therefore, this work focused on low-power and low-latency data access with minimized silicon cost. This research was implemented based on an ASIP (application specific instruction set processor) in which an ISA was based on the caffe2 inference operator and the hardware design was based on a single instruction multiple data (SIMD) architecture. The scalability and system performance of our SoC extension scheme were demonstrated. The VLIW was used to execute multiple instructions in parallel. All costs for data access time were thus eliminated for the convolution layer. Finally, the processor was synthesized based on TSMC 65 nm technology with a 200 MHz clock, and the Soc extension scheme was analyzed in an experimental model. Our design was tested on several typical neural networks, achieving 196 GOPS at 200 MHz and 241 GOPS/W on the VGG16Net and AlexNet.

Embedded UV Sensors in CMOS SOI Technology.

We report on ultraviolet (UV) sensors employing high voltage PIN lateral photodiode strings integrated into the production RF SOI (silicon on isolator) CMOS platform. The sensors were optimized for applications that require measurements of short wavelength ultraviolet (UVC) radiation under strong visible and near-infrared lights, such as UV used for sterilization purposes, e.g., COVID-19 disinfection. Responsivity above 0.1 A/W in the UVC range was achieved, and improved blindness to visible and infrared (IR) light demonstrated by implementing back-end dielectric layers transparent to the UV, in combination with differential sensing circuits with polysilicon UV filters. Degradation of the developed sensors under short wavelength UV was investigated and design and operation regimes allowing decreased degradation were discussed. Compared with other embedded solutions, the current design is implemented in a mass-production CMOS SOI technology, without additional masks, and has high sensitivity in UVC.

Rapid and specific detection of intact viral particles using functionalized microslit silicon membranes as a fouling-based sensor.

The COVID-19 pandemic demonstrated the public health benefits of reliable and accessible point-of-care (POC) diagnostic tests for viral infections. Despite the rapid development of gold-standard reverse transcription polymerase chain reaction (RT-PCR) assays for SARS-CoV-2 only weeks into the pandemic, global demand created logistical challenges that delayed access to testing for months and helped fuel the spread of COVID-19. Additionally, the extreme sensitivity of RT-PCR had a costly downside as the tests could not differentiate between patients with active infection and those who were no longer infectious but still shedding viral genomes. To address these issues for the future, we propose a novel membrane-based sensor that only detects intact virions. The sensor combines affinity and size based detection on a membrane-based sensor and does not require external power to operate or read. Specifically, the presence of intact virions, but not viral debris, fouls the membrane and triggers a macroscopically visible hydraulic switch after injection of a 40 µL sample with a pipette. The device, which we call the µSiM-DX (microfluidic device featuring a silicon membrane for diagnostics), features a biotin-coated microslit membrane with pores ∼2-3× larger than the intact virus. Streptavidin-conjugated antibody recognizing viral surface proteins are incubated with the sample for ∼1 hour prior to injection into the device, and positive/negative results are obtained within ten seconds of sample injection. Proof-of-principle tests have been performed using preparations of vaccinia virus. After optimizing slit pore sizes and porous membrane area, the fouling-based sensor exhibits 100% specificity and 97% sensitivity for vaccinia virus (n = 62). Moreover, the dynamic range of the sensor extends at least from 105.9 virions per mL to 1010.4 virions per mL covering the range of mean viral loads in symptomatic COVID-19 patients (105.6-107 RNA copies per mL). Forthcoming work will test the ability of our sensor to perform similarly in biological fluids and with SARS-CoV-2, to fully test the potential of a membrane fouling-based sensor to serve as a PCR-free alternative for POC containment efforts in the spread of infectious disease.

Ultrahigh Sensitive Au-Doped Silicon Nanomembrane Based Wearable Sensor Arrays for Continuous Skin Temperature Monitoring with High Precision.

Monitoring the body temperature with high accuracy provides a fast, facile, yet powerful route about the human body in a wide range of health information standards. Here, the first ever ultrasensitive and stretchable gold-doped silicon nanomembrane (Au-doped SiNM) epidermal temperature sensor array is introduced. The ultrasensitivity is achieved by shifting freeze-out region to intrinsic region in carrier density and modulation of fermi energy level of p-type SiNM through the development of a novel gold-doping strategy. The Au-doped SiNM is readily transferred onto an ultrathin polymer layer with a well-designed serpentine mesh structure, capable of being utilized as an epidermal temperature sensor array. Measurements in vivo and in vitro show temperature coefficient of resistance as high as -37270.72 ppm °C-1 , 22 times higher than existing metal-based temperature sensors with similar structures, and one of the highest thermal sensitivity among the inorganic material based temperature sensors. Applications in the continuous monitoring of body temperature and respiration rate during exercising are demonstrated with a successful capture of information. This work lays a foundation for monitoring body temperature, potentially useful for precision diagnosis (e.g., continuous monitoring body temperature in coronavirus disease 2019 cases) and management of disease relevance to body temperature in healthcare.

A Miniaturised, Fully Integrated NDIR CO2 Sensor On-Chip.

In this paper, we present a fully integrated Non-dispersive Infrared (NDIR) CO2 sensor implemented on a silicon chip. The sensor is based on an integrating cylinder with access waveguides. A mid-IR LED is used as the optical source, and two mid-IR photodiodes are used as detectors. The fully integrated sensor is formed by wafer bonding of two silicon substrates. The fabricated sensor was evaluated by performing a CO2 concentration measurement, showing a limit of detection of ∼750 ppm. The cross-sensitivity of the sensor to water vapor was studied both experimentally and numerically. No notable water interference was observed in the experimental characterizations. Numerical simulations showed that the transmission change induced by water vapor absorption is much smaller than the detection limit of the sensor. A qualitative analysis on the long term stability of the sensor revealed that the long term stability of the sensor is subject to the temperature fluctuations in the laboratory. The use of relatively cheap LED and photodiodes bare chips, together with the wafer-level fabrication process of the sensor provides the potential for a low cost, highly miniaturized NDIR CO2 sensor.

Label-free detection of virus-like particles employing rotationally symmetric nanowire array based whispering gallery and quasi-whispering gallery resonant modes onto a silicon platform.

In spite of tremendous advancements in modern diagnostics, there is a dire need for reliable, label-free detection of highly contagious pathogens like viruses. In view of the limitations of existing diagnostic techniques, the present theoretical study proposes a novel scheme of detecting virus-like particles employing whispering gallery and quasi-whispering gallery resonant modes of a composite optical system. Whereas whispering gallery mode (WGM) resonators are conventionally realized using micro-disk, -ring, -toroid or spherical structures, the present study utilizes a rotationally symmetric array of silicon nanowires which offers higher sensitivity compared to the conventional WGM resonator while detecting virus-like particles. Notwithstanding the relatively low quality factor of the system, the underlying multiple-scattering mediated photon entrapment, coupled with peripheral total-internal reflection, results in high fidelity of the system against low signal-to-noise ratio. Finite difference time domain based numerical analysis has been performed to correlate resonant modes of the array with spatial location of the virus. The correlation has been subsequently utilized for statistical analysis of simulated test cases. Assuming detection to be limited by resolution of the measurement system, results of the analysis suggest that for only about 5% of the simulate test cases the resonant wavelength shift lies within the minimum detection range of 0.001-0.01 nm. For a single virus of 160 nm diameter, more than 8 nm shift of the resonant mode and nearly 100% change of quality factor are attained with the proposed nanowire array based photonic structure.

Using a roller pump for establishing extra-corporal membrane oxygenation (ECMO) - technical considerations for times of crisis.

OBJECTIVE: The COVID-19 pandemic requires thinking about alternatives to establish ECMO when often-limited hardware resources are exhausted. Heart-lung-machines may potentially be used for ECMO but contain roller pumps as compared to centrifugal pumps in ECMO-circuits. We here tested roller pumps as rescue pump for ECMO-establishment. METHODS: We set up in vitro circuits on roller pumps from C5 heart-lung-machine with 5 l/minutes flow. In two series, we placed either PVC or silicon tubing for an ECMO circuit into the roller pump. We assessed the mechanical stress on the tubing (aiming to run the pump for at least 1 week), measured the temperature increase generated by the friction and assessed flow characteristics and its measurement in simulated situations resembling tube kinking and suction. RESULTS: The roller pumps led to expected and unexpected adverse events. PVC tubing burst between 36 and 78 hours, while silicon tubing lasted for at least 7 days. At 7 days, the silicone tubing showed significant signs of roller pump wear visible on the outside. The inside, however, was free of surface irregularities. Using these tubings in a roller pump led to a remarkable increase in circuit temperature (PVC: +12.0°C, silicone +2.9°C). Kinking or suction on the device caused the expected dramatic flow reduction (as assessed by direct measurement) while the roller pump display continued to show the preset flow. The roller pump is therefore not able to reliably determine the true flow rate. CONCLUSION: Roller pumps with silicone tubing but not PVC tubing may be used for running ECMO circuits. Silicone tubing may endure the roller pump shear forces for up to 1 week. Thus, repeated tubing repositioning may be a solution. Circuit heating and substantial limitations in flow detection should increase attention if clinical use in situations of crisis is considered.

Surface Biochemical Modification of Poly(dimethylsiloxane) for Specific Immune Cytokine Response.

Recent evidence suggests that proinflammatory cytokines, such as tumor necrosis factor α (TNF-α), play a pivotal role in the development of inflammatory-related pathologies (covid-19, depressive disorders, sepsis, cancer, etc.,). More importantly, the development of TNF-α biosensors applied to biological fluids (e.g. sweat) could offer non-invasive solutions for the continuous monitoring of these disorders, in particular, polydimethylsiloxane (PDMS)-based biosensors. We have therefore investigated the biofunctionalization of PDMS surfaces using a silanization reaction with 3-aminopropyltriethoxysilane, for the development of a human TNF-α biosensor. The silanization conditions for 50 µm PDMS surfaces were extensively studied by using water contact angle measurements, electron dispersive X-ray and Fourier transform infrared spectroscopies, and fluorescamine detection. Evaluation of the wettability of the silanized surfaces and the Si/C ratio pointed out to the optimal silanization conditions supporting the formation of a stable and reproducible aminosilane layer, necessary for further bioconjugation. An ELISA-type immunoassay was then successfully performed for the detection and quantification of human TNF-α through fluorescent microscopy, reaching a limit of detection of 0.55 µg/mL (31.6 nM). Finally, this study reports for the first time a promising method for the development of PDMS-based biosensors for the detection of TNF-α, using a quick, stable, and simple biofunctionalization process.

Disposable silicon-based all-in-one micro-qPCR for rapid on-site detection of pathogens.

Rapid screening and low-cost diagnosis play a crucial role in choosing the correct course of intervention when dealing with highly infectious pathogens. This is especially important if the disease-causing agent has no effective treatment, such as the novel coronavirus SARS-CoV-2, and shows no or similar symptoms to other common infections. Here, we report a disposable silicon-based integrated Point-of-Need transducer (TriSilix) for real-time quantitative detection of pathogen-specific sequences of nucleic acids. TriSilix can be produced at wafer-scale in a standard laboratory (37 chips of 10 × 10 × 0.65 mm in size can be produced in 7 h, costing ~0.35 USD per device). We are able to quantitatively detect a 563 bp fragment of genomic DNA of Mycobacterium avium subspecies paratuberculosis through real-time PCR with a limit-of-detection of 20 fg, equivalent to a single bacterium, at the 35th cycle. Using TriSilix, we also detect the cDNA from SARS-CoV-2 (1 pg) with high specificity against SARS-CoV (2003).

Luminescent silicon nanostructures and COVID-19.

This Faraday Discussion volume is unique in the hundred plus year history of the Faraday Discussion series, being produced at a time of unprecedented circumstances worldwide and without the preceding Faraday Discussion conference having taken place.