RESUMEN

Sensitive magnetic nucleic acid (NA) detection via frequency mixing magnetic detection (FMMD) requires amplified NA samples for which a reliable temperature control is necessary. The feasibility of recombinase polymerase amplification (RPA) was studied within a newly integrated temperature-controlled sensor unit of a mobile FMMD based setup. It has been demonstrated that the inherently generated heat of the low frequency (LF) excitation signal of FMMD can be utilized and controlled by means of pulse width modulation (PWM). To test control performance in a point of care (PoC) setting with changing ambient conditions, a steady state and dynamic response model for the thermal behavior at the sample position of the sensor were developed. We confirmed that in the sensor unit of the FMMD device, RPA performs similar as in a temperature-controlled water bath. For narrow steady state temperature regions, a linear extrapolation suffices for estimation of the sample position temperature, based on the temperature feedback sensor for PWM control. For any other ambient conditions, we identified and validated a lumped parameter model (LPM) performing with high estimation accuracy. We expect that the method can be used for NA amplification and magnetic detection using FMMD in resource-limited settings.

RESUMEN

Frequency mixer is an essential block in radio-frequency signal processing for frequency translation and phase comparison. The most common mixers are fabricated using passive elements which suffer from significant conversion loss and low isolation. Mixers using active devices are used less frequently and rather less matured on GaN technology. Here, we demonstrate a mixer based on GaN split-gate nanowire transistor, allowing low conversion loss and high isolation. A constriction is formed by electrostatic modulation of the effective gate width. The threshold voltage of the transistor is modified by one of the gate voltages through the width variation, while the other gate voltage biases the transistor in the saturation region. The nonlinear dependency of the transistor characteristics on the two gate voltages facilitates frequency translation. The mixing characteristics of this architecture are verified both experimentally and theoretically. The output power spectral density peaks at the difference frequency with a minimal conversion loss. Extremely high isolation is measured using three-port S-parameter measurements. The proposed architecture shows multiple benefits, additionally facilitating monolithic mixers on the GaN platform.

RESUMEN

Magnetic nanoparticles (MNPs), particularly iron oxide nanoparticles (IONPs), play a pivotal role in biomedical applications ranging from magnetic resonance imaging (MRI) enhancement and cancer hyperthermia treatments to biosensing. This study focuses on the synthesis, characterization, and application of IONPs with two different size distributions for frequency mixing magnetic detection (FMMD), a technique that leverages the nonlinear magnetization properties of MNPs for sensitive biosensing. IONPs are synthesized through thermal decomposition and subsequent growth steps. Our findings highlight the critical influence of IONP size on the FMMD signal, demonstrating that larger particles contribute dominantly to the FMMD signal. This research advances our understanding of IONP behavior, underscoring the importance of size in their application in advanced diagnostic tools.

RESUMEN

A signal mixer facilitates rich computation, which has been the building block of modern telecommunication. This frequency mixing produces new signals at the sum and difference frequencies of input signals, enabling powerful operations such as heterodyning and multiplexing. Here, we report that a neuron is a signal mixer. We found through ex vivo and in vivo whole-cell measurements that neurons mix exogenous (controlled) and endogenous (spontaneous) subthreshold membrane potential oscillations, producing new oscillation frequencies, and that neural mixing originates in voltage-gated ion channels. Furthermore, we demonstrate that mixing is evident in human brain activity and is associated with cognitive functions. We found that the human electroencephalogram displays distinct clusters of local and inter-region mixing and that conversion of the salient posterior alpha-beta oscillations into gamma-band oscillations regulates visual attention. Signal mixing may enable individual neurons to sculpt the spectrum of neural circuit oscillations and utilize them for computational operations.

Asunto(s)

RESUMEN

Different from the traditional frequency-mixing technique which employs a contacting transducer, the laser-induced acoustic nonlinear frequency-mixing detection technique utilizes a laser source to instigate crack motion and generate acoustic waves. Thus, apart from the temperature oscillation induced by the pump laser, the "basic temperature" originating from the probe laser can also influence the crack. This additional variable complicates the contact state of the crack, yielding a more diverse range of nonlinear acoustic signal attributes. In light of this, our study enhances the conventional opto-acoustic nonlinear frequency mixing experimental setup by integrating an independent heating laser beam. This modification isolates the impact of the "basic temperature" on crack width while also dialing down the probe laser power to mitigate its thermal effects. To amplify the sensitivity of crack detection, we deliberated on the optimal laser source parameters for this setup. Consequently, our revamped system, paired with fine-tuned parameters, captures nonlinear acoustic signals with an enriched feature set. This investigation can provide support for the non-contact opto-acoustic nonlinear frequency mixing technique in the detection and evaluation of micro-cracks.

RESUMEN

Voltage-controlled oscillators, serving as fundamental components in semiconductor chips, find extensive applications in diverse modules such as phase-locked loops, clock generators, and frequency synthesizers within high-frequency integrated circuits. This study marks the first implementation of superconducting Josephson probe microscopy for near-field microwave detection on multiple voltage-controlled oscillators. Focusing on spectrum tracking, various phenomena, such as stray spectra and frequency drifts, were found under nonsteady operating states. Parasitic electromagnetic fields, originating from power supply lines and frequency divider circuits, were identified as sources of interference between units. The investigation further determined optimal working states by analyzing features of the microwave distributions. Our research not only provides insights into the optimization of circuit design and performance enhancement in oscillators but also emphasizes the significance of nondestructive near-field microwave microscopy as a pivotal tool in characterizing integrated millimeter-wave chips.

RESUMEN

Frequency mixing magnetic detection (FMMD) is a sensitive and selective technique to detect magnetic nanoparticles (MNPs) serving as probes for binding biological targets. Its principle relies on the nonlinear magnetic relaxation dynamics of a particle ensemble interacting with a dual frequency external magnetic field. In order to increase its sensitivity, lower its limit of detection and overall improve its applicability in biosensing, matching combinations of external field parameters and internal particle properties are being sought to advance FMMD. In this study, we systematically probe the aforementioned interaction with coupled Néel-Brownian dynamic relaxation simulations to examine how key MNP properties as well as applied field parameters affect the frequency mixing signal generation. It is found that the core size of MNPs dominates their nonlinear magnetic response, with the strongest contributions from the largest particles. The drive field amplitude dominates the shape of the field-dependent response, whereas effective anisotropy and hydrodynamic size of the particles only weakly influence the signal generation in FMMD. For tailoring the MNP properties and parameters of the setup towards optimal FMMD signal generation, our findings suggest choosing large particles of core sizes dC>25 nm with narrow size distributions (σ<0.1) to minimize the required drive field amplitude. This allows potential improvements of FMMD as a stand-alone application, as well as advances in magnetic particle imaging, hyperthermia and magnetic immunoassays.

RESUMEN

Photo-thermal modulation-based nonlinear opto-acoustic frequency-mixing technique is an effective method for detecting micro-cracks. When using this technique for micro-crack detection, the selection of laser source parameters is particularly crucial. Compared to traditional piezo-transducer-based mixing techniques, the characteristic of using a laser as the detection source is the presence of thermal effects. The thermal effect caused by laser irradiation on the sample surface can not only generate acoustic waves but also affect the crack state, thus influencing nonlinear signals. In this paper, an experimental setup using photo-thermal modulation-based nonlinear opto-acoustic frequency-mixing technique has been set up to investigate the thermal effects of the probe laser source. In addition, a corresponding physical model has been established to discuss the physical mechanisms revealed by the experimental results. This study provides a basis for selecting appropriate probe source parameters and scanning positions of laser sources when detecting micro-cracks using the photo-thermal modulation-based nonlinear opto-acoustic frequency-mixing technique.

RESUMEN

In this study, we propose an efficient field-free line (FFL) generator for mechanically driven FFL magnetic particle imaging (MPI) applications. The novel FFL generator comprises pairs of Halbach arrays and bar magnets. The proposed design generates high-gradient FFLs with low-mass permanent magnets, realizing fine spatial resolutions in MPI. We investigate the magnetic field generated using simulations and experiments. Our results show that the FFL generator yields a high gradient of 4.76 T/m at a cylindrical field of view of 30 mm diameter and a 70 mm open bore. A spatial resolution of less than 3.5 mm was obtained in the mechanically driven FFL-MPI.

RESUMEN

Frequency-mixing technology has been widely used to precisely identify magnetic nanoparticles in applications of quantitative biomedical detection in recent years. Examples include immune adsorption, lateral flow assays (LFAs), and biomagnetic imaging. However, the signals of magnetic response generated by adjacent magnetic samples interfere with each other owing to the small spacing between them in applications involving multi-sample detection (such as the LFA and multiplexing detection). Such signal interference prevents the biosensor from obtaining characteristic peaks related to the concentration of adjacent biomarkers from the magnetic response signals. Mathematical and physical models of the structure of sensors based on frequency-mixing techniques were developed. The theoretical model was verified and its key parameters were optimized by using simulations. A new frequency-mixing magnetic sensor structure was then designed and developed based on the model, and the key technical problem of signal crosstalk between adjacent samples was structurally solved. Finally, standard cards with stable magnetic properties were used to evaluate the performance of the sensor, and strips of the gastrin-17 (G-17) LFA were used to evaluate its potential for use in clinical applications. The results show that the minimum spacing between samples required by the optimized sensor to accurately identify them was only about 4-5 mm, and the minimum detectable concentration of G-17 was 11 pg mL-1 . This is a significant reduction in the required spacing between samples for multiplexing detection. The optimized sensor also has the potential for use in multi-channel synchronous signal acquisition, and can be used to detect synchronous magnetic signals in vivo.

Asunto(s)

RESUMEN

Due to the limitations of conventional Brucella detection methods, including safety concerns, long incubation times, and limited specificity, the development of a rapid, selective, and accurate technique for the early detection of Brucella in livestock animals is crucial to prevent the spread of the associated disease. In the present study, we introduce a magnetic nanoparticle marker-based biosensor using frequency mixing magnetic detection for point-of-care testing and quantification of Brucella DNA. Superparamagnetic nanoparticles were used as magnetically measured markers to selectively detect the target DNA hybridized with its complementary capture probes immobilized on a porous polyethylene filter. Experimental conditions like density and length of the probes, hybridization time and temperature, and magnetic binding specificity, sensitivity, and detection limit were investigated and optimized. Our sensor demonstrated a relatively fast detection time of approximately 10 min, with a detection limit of 55 copies (0.09 fM) when tested using DNA amplified from Brucella genetic material. In addition, the detection specificity was examined using gDNA from Brucella and other zoonotic bacteria that may coexist in the same niche, confirming the method's selectivity for Brucella DNA. Our proposed biosensor has the potential to be used for the early detection of Brucella bacteria in the field and can contribute to disease control measures.

Asunto(s)

RESUMEN

Frequency mixing magnetic detection (FMMD) has been explored for its applications in fields of magnetic biosensing, multiplex detection of magnetic nanoparticles (MNP) and the determination of core size distribution of MNP samples. Such applications rely on the application of a static offset magnetic field, which is generated traditionally with an electromagnet. Such a setup requires a current source, as well as passive or active cooling strategies, which directly sets a limitation based on the portability aspect that is desired for point of care (POC) monitoring applications. In this work, a measurement head is introduced that involves the utilization of two ring-shaped permanent magnets to generate a static offset magnetic field. A steel cylinder in the ring bores homogenizes the field. By variation of the distance between the ring magnets and of the thickness of the steel cylinder, the magnitude of the magnetic field at the sample position can be adjusted. Furthermore, the measurement setup is compared to the electromagnet offset module based on measured signals and temperature behavior.

Asunto(s)

RESUMEN

Nanomaterials, especially superparamagnetic nanomaterials, have recently played essential roles in point-of-care testing due to their intrinsic magnetic, electrochemical, and optical properties. The inherent superparamagnetism of magnetic nanoparticles makes them highly sensitive for quantitative detection. Among the various magnetic detection technologies, frequency mixing technology (FMT) technology is an emerging detection technique in the nanomedical field. FMT sensors have high potential for development in the field of biomedical quantitative detection due to their simple structure, and they are not limited to the materials used. In particular, they can be applied for large-scale disease screening, early tumor marker detection, and low-dose drug detection. This review summarizes the principles of FMT and recent advances in the fields of immunoadsorption, lateral flow assay detection, magnetic imaging, and magnetic nanoparticles recognition. The advantages and limitations of FMT sensors for robust, ultrasensitive biosensing are highlighted. Finally, the future requirements and challenges in the development of this technology are described. This review provides further insights for researchers to inspire the future development of FMT by integration into biosensing and devices with a broad field of applications in analytical sensing and clinical usage.

Asunto(s)

RESUMEN

Magnetic immunoassays employing Frequency Mixing Magnetic Detection (FMMD) have recently become increasingly popular for quantitative detection of various analytes. Simultaneous analysis of a sample for two or more targets is desirable in order to reduce the sample amount, save consumables, and save time. We show that different types of magnetic beads can be distinguished according to their frequency mixing response to a two-frequency magnetic excitation at different static magnetic offset fields. We recorded the offset field dependent FMMD response of two different particle types at frequencies f1 + n⋅f2, n = 1, 2, 3, 4 with f1 = 30.8 kHz and f2 = 63 Hz. Their signals were clearly distinguishable by the locations of the extremes and zeros of their responses. Binary mixtures of the two particle types were prepared with different mixing ratios. The mixture samples were analyzed by determining the best linear combination of the two pure constituents that best resembled the measured signals of the mixtures. Using a quadratic programming algorithm, the mixing ratios could be determined with an accuracy of greater than 14%. If each particle type is functionalized with a different antibody, multiplex detection of two different analytes becomes feasible.

Asunto(s)

RESUMEN

Dual frequency magnetic excitation of magnetic nanoparticles (MNP) enables enhanced biosensing applications. This was studied from an experimental and theoretical perspective: nonlinear sum-frequency components of MNP exposed to dual-frequency magnetic excitation were measured as a function of static magnetic offset field. The Langevin model in thermodynamic equilibrium was fitted to the experimental data to derive parameters of the lognormal core size distribution. These parameters were subsequently used as inputs for micromagnetic Monte-Carlo (MC)-simulations. From the hysteresis loops obtained from MC-simulations, sum-frequency components were numerically demodulated and compared with both experiment and Langevin model predictions. From the latter, we derived that approximately 90% of the frequency mixing magnetic response signal is generated by the largest 10% of MNP. We therefore suggest that small particles do not contribute to the frequency mixing signal, which is supported by MC-simulation results. Both theoretical approaches describe the experimental signal shapes well, but with notable differences between experiment and micromagnetic simulations. These deviations could result from Brownian relaxations which are, albeit experimentally inhibited, included in MC-simulation, or (yet unconsidered) cluster-effects of MNP, or inaccurately derived input for MC-simulations, because the largest particles dominate the experimental signal but concurrently do not fulfill the precondition of thermodynamic equilibrium required by Langevin theory.

RESUMEN

The misuse of antibiotics as well as incorrect dosage or insufficient time for detoxification can result in the presence of pharmacologically active molecules in fresh milk. Hence, in many countries, commercially available milk has to be tested with immunological, chromatographic or microbiological analytical methods to avoid consumption of antibiotic residues. Here a novel, sensitive and portable assay setup for the detection and quantification of penicillin and kanamycin in whole fat milk (WFM) based on competitive magnetic immunodetection (cMID) is described and assay accuracy determined. For this, penicillin G and kanamycin-conjugates were generated and coated onto a matrix of immunofiltration columns (IFC). Biotinylated penicillin G or kanamycin-specific antibodies were pre-incubated with antibiotics-containing samples and subsequently applied onto IFC to determine the concentration of antibiotics through the competition of antibody-binding to the antibiotic-conjugate molecules. Bound antibodies were labeled with streptavidin-coated magnetic particles and quantified using frequency magnetic mixing technology. Based on calibration measurements in WFM with detection limits of 1.33 ng·mL-1 for penicillin G and 1.0 ng·mL-1 for kanamycin, spiked WFM samples were analyzed, revealing highly accurate recovery rates and assay precision. Our results demonstrate the suitability of cMID-based competition assay for reliable and easy on-site testing of milk.

RESUMEN

Whereas most of the reports on the nonlinear properties of micro- and nanostructures address the generation of distinct signals, such as second or third harmonic, here we demonstrate that the novel generation of dual output lasers recently developed for microscopy can readily increase the accessible parameter space and enable the simultaneous excitation and detection of multiple emission orders such as several harmonics and signals stemming from various sum and difference frequency mixing processes. This rich response, which in our case features 10 distinct emissions and encompasses the whole spectral range from the deep ultraviolet to the short-wave infrared region, is demonstrated using various nonlinear oxide nanomaterials while being characterized and simulated temporally and spectrally. Notably, we show that the response is conserved when the particles are embedded in biological media opening the way to novel biolabeling and phototriggering strategies.

Asunto(s)

RESUMEN

Second harmonic generation (SHG) and frequency mixing of electrical signals are fundamental for a wide range of radiofrequency applications. Recently, ferroelectric field-effect transistors (FeFETs), made from ferroelectric hafnium oxide (HfO2), have demonstrated promising SHG capabilities because of their unique symmetric transfer curves. In this paper, we illustrate how this symmetry is highly sensitive to material properties by varying the thickness of the ferroelectric layer and the doping of the silicon substrate. We show that the SHG conversion gain and the spectral purity are greatly increased (up to 96%) by precisely tuning the ferroelectric polarization reversal and the quantum tunneling currents. Based on this, we propose and experimentally demonstrate the generation of the difference and of the sum of two input frequencies (frequency mixing) with a single FeFET, which we attribute to the inherently strong quadratic component of the symmetric transfer characteristics. Because of the reversible and continuous ferroelectric switching in HfO2, our approach allows for an electrical control of the energy distribution of spectral components, thus opening up new and very promising paths for frequency manipulations with simple ferroelectric devices.

RESUMEN

A new approach to nonlinear frequency mixing based on local damage resonance is proposed, analysed and tested experimentally for flexural waves in composites. The method is free from stringent requirements on the mode types and frequencies for interacting waves. The resonance of damage enhances strongly its higher-order nonlinear response and boosts the efficiency of generation for numerous-order combination frequencies. The damage resonance combined with its strong nonlinearity also provides locality of nonlinear interaction even for continuous wave operation. The combination frequencies generated locally in the damaged area are the footprints of damage and used for its detection, location and visualization. A single C-scan yields a number of images of the defect corresponding to various nonlinearly generated frequencies. Various versions of the resonant frequency mixing are considered and applied to nonlinear imaging of defects in composite materials.

RESUMEN

Food and crop contaminations with mycotoxins are a severe health risk for consumers and cause high economic losses worldwide. Currently, different chromatographic- and immuno-based methods are used to detect mycotoxins within different sample matrices. There is a need for novel, highly sensitive detection technologies that avoid time-consuming procedures and expensive laboratory equipment but still provide sufficient sensitivity to achieve the mandated detection limit for mycotoxin content. Here we describe a novel, highly sensitive, and portable aflatoxin B1 detection approach using competitive magnetic immunodetection (cMID). As a reference method, a competitive ELISA optimized by checkerboard titration was established. For the novel cMID procedure, immunofiltration columns, coated with aflatoxin B1-BSA conjugate were used for competitive enrichment of biotinylated aflatoxin B1-specific antibodies. Subsequently, magnetic particles functionalized with streptavidin can be applied to magnetically label retained antibodies. By means of frequency mixing technology, particles were detected and quantified corresponding to the aflatoxin content in the sample. After the optimization of assay conditions, we successfully demonstrated the new competitive magnetic detection approach with a comparable detection limit of 1.1 ng aflatoxin B1 per ml sample to the cELISA reference method. Our results indicate that the cMID is a promising method reducing the risks of processing contaminated commodities.

Asunto(s)