Dielectric Detection of Single Nanoparticles Using a Microwave Resonator Integrated with a Nanopore.

The characterization of individual nanoparticles in a liquid constitutes a critical challenge for the environmental, material, and biological sciences. To detect nanoparticles, electronic approaches are especially desirable owing to their compactness and lower costs. While electronic detection in the form of resistive-pulse sensing has enabled the acquisition of geometric properties of various analytes, impedimetric measurements to obtain dielectric signatures of nanoparticles have scarcely been reported. To explore this orthogonal sensing modality, we developed an impedimetric sensor based on a microwave resonator with a nanoscale sensing gap surrounding a nanopore built on a 220 nm silicon nitride membrane. The microwave resonator has a coplanar waveguide configuration with a resonance frequency of approximately 6.6 GHz. The approach of single nanoparticles near the sensing region and their translocation through the nanopores induced sudden changes in the impedance of the structure. The impedance changes, in turn, were picked up by the phase response of the microwave resonator. We worked with 100 and 50 nm polystyrene nanoparticles to observe single-particle events. Our current implementation was limited by the nonuniform electric field at the sensing region. This work provides a complementary sensing modality for nanoparticle characterization, where the dielectric response, rather than ionic current, determines the signal.

Atmospheric-Pressure Mass Spectrometry by Single-Mode Nanoelectromechanical Systems.

Weighing particles above the megadalton mass range has been a persistent challenge in commercial mass spectrometry. Recently, nanoelectromechanical systems-based mass spectrometry (NEMS-MS) has shown remarkable performance in this mass range, especially with the advance of performing mass spectrometry under entirely atmospheric conditions. This advance reduces the overall complexity and cost while increasing the limit of detection. However, this technique required the tracking of two mechanical modes and the accurate knowledge of mode shapes that may deviate from their ideal values, especially due to air damping. Here, we used a NEMS architecture with a central platform, which enables the calculation of mass by single-mode measurements. Experiments were conducted using polystyrene and gold nanoparticles to demonstrate the successful acquisition of mass spectra using a single mode with an improved areal capture efficiency. This advance represents a step forward in NEMS-MS, bringing it closer to becoming a practical application for the mass sensing of nanoparticles.

Leveraging the elastic deformability of polydimethylsiloxane microfluidic channels for efficient intracellular delivery.

With the rapid development of microfluidic based cell therapeutics systems, the need arises for compact, modular, and microfluidics-compatible intracellular delivery platforms with small footprints and minimal operational requirements. Physical deformation of cells passing through a constriction in a microfluidic channel has been shown to create transient membrane perturbations that allow passive diffusion of materials from the outside to the interior of the cell. This mechanical approach to intracellular delivery is simple to implement and fits the criteria outlined above. However, available microfluidic platforms that operate through this mechanism are traditionally constructed from rigid channels with fixed dimensions that suffer from irreversible clogging and incompatibility with larger size distributions of cells. Here we report a flexible and elastically deformable microfluidic channel, and we leverage this elasticity to dynamically generate temporary constrictions with any given size within the channel width parameters. Additionally, clogging is prevented by increasing the size of the constriction momentarily to allow clogs to pass. By tuning the size of the constriction appropriately, we show the successful delivery of GFP-coding plasmids to the interior of three mammalian cell lines and fluorescent gold nanoparticles to HEK293 FT cells all the while maintaining a high cell viability rate. We also demonstrate the device capabilities by systematically identifying the optimum constriction size that maximizes the intracellular delivery efficiency of FITC-dextran for three different cell lines. This development will no doubt lead to miniaturized intracellular delivery microfluidic components that can be easily integrated into larger lab-on-a-chip systems for future cell modification devices.

Atmospheric Pressure Mass Spectrometry of Single Viruses and Nanoparticles by Nanoelectromechanical Systems.

Mass spectrometry of intact nanoparticles and viruses can serve as a potent characterization tool for material science and biophysics. Inaccessible by widespread commercial techniques, the mass of single nanoparticles and viruses (>10MDa) can be readily measured by nanoelectromechanical systems (NEMS)-based mass spectrometry, where charged and isolated analyte particles are generated by electrospray ionization (ESI) in air and transported onto the NEMS resonator for capture and detection. However, the applicability of NEMS as a practical solution is hindered by their miniscule surface area, which results in poor limit-of-detection and low capture efficiency values. Another hindrance is the necessity to house the NEMS inside complex vacuum systems, which is required in part to focus analytes toward the miniscule detection surface of the NEMS. Here, we overcome both limitations by integrating an ion lens onto the NEMS chip. The ion lens is composed of a polymer layer, which charges up by receiving part of the ions incoming from the ESI tip and consequently starts to focus the analytes toward an open window aligned with the active area of the NEMS electrostatically. With this integrated system, we have detected the mass of gold and polystyrene nanoparticles under ambient conditions and with two orders-of-magnitude improvement in capture efficiency compared to the state-of-the-art. We then applied this technology to obtain the mass spectrum of SARS-CoV-2 and BoHV-1 virions. With the increase in analytical throughput, the simplicity of the overall setup, and the operation capability under ambient conditions, the technique demonstrates that NEMS mass spectrometry can be deployed for mass detection of engineered nanoparticles and biological samples efficiently.

Frequency-Dependent Piezoresistive Effect in Top-down Fabricated Gold Nanoresistors.

Piezoresistive strain gauges allow for electronic readout of mechanical deformations with high fidelity. As piezoresistive strain gauges are aggressively being scaled down for applications in nanotechnology, it has become critical to investigate their physical attributes at different limits. Here, we describe an experimental approach for studying the piezoresistive gauge factor of a gold thin-film nanoresistor as a function of frequency. The nanoresistor is fabricated lithographically near the anchor of a nanomechanical doubly clamped beam resonator. As the resonator is driven to resonance in one of its normal modes, the nanoresistor is exposed to frequency-dependent strains of ε ≲ 10-5 in the 4-36 MHz range. We calibrate the strain using optical interferometry and measure the resistance changes using a radio frequency mix-down technique. The piezoresistive gauge factor γ of our lithographic gold nanoresistors is γ ≈ 3.6 at 4 MHz, in agreement with comparable macroscopic thin metal film resistors in previous works. However, our γ values increase monotonically with frequency and reach γ ≈ 15 at 36 MHz. We discuss possible physics that may give rise to this unexpected frequency dependence.

Nanomechanical Measurement of the Brownian Force Noise in a Viscous Liquid.

We study the frequency spectrum of the thermal force giving rise to Brownian motion of a nanomechanical beam resonator in a viscous liquid. In the first set of experiments, we measure the power spectral density (PSD) of the position fluctuations of the resonator around its fundamental mode at its center. Then, we measure the frequency-dependent linear response of the resonator, again at its center, by driving it with a harmonic force that couples well to the fundamental mode. These two measurements allow us to determine the PSD of the Brownian force noise acting on the structure in its fundamental mode. The PSD of the force noise from multiple resonators spanning a broad frequency range displays a "colored spectrum" and follows the dissipation of a blade oscillating in a viscous liquid-by virtue of the fluctuation-dissipation theorem of statistical mechanics.

Observation of coupled mechanical resonance modes within suspended 3D nanowire arrays.

Complex yet compact nanoscale mechanisms have largely been absent due to the rather limited availability of components and integration techniques. Especially missing have been efficient interconnects with adjustable characteristics. To address this issue, we report here, for the first time, the transduction of collective modes in vertically stacked arrays of silicon nanowires suspended between couplers. In addition to the ambitious miniaturization, this composite resonator enables the control of coupling strength through the lithographic definition of coupler stiffness. A direct link is thus established between coupling strength and spectral response for two array architectures with nominally identical resonators but different couplers. A series of unique observations emerged in this platform, such as the splitting of a single mode into two closely spaced modes which raises the possibility of tunable bandpass filters with enhanced spectrum characteristics. Finally, intermodal coupling strengths were measured providing strong evidence about the collective nature of these modes.

Full Electrostatic Control of Nanomechanical Buckling.

Buckling of mechanical structures results in bistable states with spatial separation, a feature desirable for sensing, shape configuration, and mechanical computation. Although different approaches have been developed to access buckling at microscopic scales, such as heating or prestressing beams, little attention has been paid so far to dynamically control all the parameters critical for the bifurcation-the compressive stress and the lateral force on the beam. Here, we develop an all-electrostatic architecture to control the compressive force, as well as the direction and amount of buckling, without significant heat generation on micro- or nanostructures. With this architecture, we demonstrated fundamental aspects of device function and dynamics. By applying voltages at any of the digital electronics standards, we have controlled the direction of buckling. Lateral deflections as large as 12% of the beam length were achieved. By modulating the compressive stress and lateral electrostatic force acting on the beam, we tuned the potential energy barrier between the postbifurcation stable states and characterized snap-through transitions between these states. The proposed architecture opens avenues for further studies in actuators, shape-shifting devices, thermodynamics of information, and dynamical chaos.

Nonlinear Nanomechanical Mass Spectrometry at the Single-Nanoparticle Level.

Nanoelectromechanical systems (NEMS) have emerged as a promising technology for performing the mass spectrometry of large biomolecules and nanoparticles. As nanoscale objects land on NEMS sensors one by one, they induce resolvable shifts in the resonance frequency of the sensor proportional to their weight. The operational regime of NEMS sensors is often limited by the onset of nonlinearity, beyond which the highly sensitive schemes based on frequency tracking by phase-locked loops cannot be readily used. Here, we develop a measurement architecture with which to operate at the nonlinear regime and measure frequency shifts induced by analytes in a rapid and sensitive manner. We used this architecture to individually characterize the mass of gold nanoparticles and verified the results by performing independent measurements of the same nanoparticles based on linear mass sensing. Once the feasibility of the technique is established, we have obtained the mass spectrum of a 20 nm gold nanoparticle sample by individually recording about 500 single-particle events using two modes working sequentially in the nonlinear regime. The technique obtained here can be used for thin nanomechanical structures that possess a limited dynamic range.

Correction: Towards microwave imaging of cells.

Correction for 'Towards microwave imaging of cells' by Mehmet Kelleci et al., Lab Chip, 2018, DOI: 10.1039/c7lc01251a.

Mass Spectrometry Using Nanomechanical Systems: Beyond the Point-Mass Approximation.

The mass measurement of single molecules, in real time, is performed routinely using resonant nanomechanical devices. This approach models the molecules as point particles. A recent development now allows the spatial extent (and, indeed, image) of the adsorbate to be characterized using multimode measurements ( Hanay , M. S. , Nature Nanotechnol. , 10 , 2015 , pp 339 - 344 ). This "inertial imaging" capability is achieved through virtual re-engineering of the resonator's vibrating modes, by linear superposition of their measured frequency shifts. Here, we present a complementary and simplified methodology for the analysis of these inertial imaging measurements that exhibits similar performance while streamlining implementation. This development, together with the software that we provide, enables the broad implementation of inertial imaging that opens the door to a range of novel characterization studies of nanoscale adsorbates.

Towards microwave imaging of cells.

Integrated detection techniques that can characterize the morphological properties of cells are needed for the widespread use of lab-on-a-chip technology. Herein, we establish a theoretical and experimental framework to use resonant microwave sensors in their higher order modes so that the morphological properties of analytes inside a microfluidic channel can be obtained electronically. We built a phase-locked loop system that can track the first two modes of a microstrip line resonator to detect the size and location of microdroplets and cells passing through embedded microfluidic channels. The attained resolution, expressed in terms of Allan deviation at the response time, is as small as 2 × 10-8 for both modes. Additionally, simulations were performed to show that sensing with higher order modes can yield the geometrical volume, effective permittivity, two-dimensional extent, and the orientation of analytes. The framework presented here makes it possible to develop a novel type of microscope that operates at the microwave band, i.e., a radar for cells.

Inertial imaging with nanomechanical systems.

Mass sensing with nanoelectromechanical systems has advanced significantly during the last decade. With nanoelectromechanical systems sensors it is now possible to carry out ultrasensitive detection of gaseous analytes, to achieve atomic-scale mass resolution and to perform mass spectrometry on single proteins. Here, we demonstrate that the spatial distribution of mass within an individual analyte can be imaged--in real time and at the molecular scale--when it adsorbs onto a nanomechanical resonator. Each single-molecule adsorption event induces discrete, time-correlated perturbations to all modal frequencies of the device. We show that by continuously monitoring a multiplicity of vibrational modes, the spatial moments of mass distribution can be deduced for individual analytes, one-by-one, as they adsorb. We validate this method for inertial imaging, using both experimental measurements of multimode frequency shifts and numerical simulations, to analyse the inertial mass, position of adsorption and the size and shape of individual analytes. Unlike conventional imaging, the minimum analyte size detectable through nanomechanical inertial imaging is not limited by wavelength-dependent diffraction phenomena. Instead, frequency fluctuation processes determine the ultimate attainable resolution. Advanced nanoelectromechanical devices appear capable of resolving molecular-scale analytes.