A Hybrid Orbitrap-Nanoelectromechanical Systems Approach for the Analysis of Individual, Intact Proteins in Real Time.

Nanoelectromechanical systems (NEMS)-based mass spectrometry (MS) is an emerging technique that enables determination of the mass of individual adsorbed particles by driving nanomechanical devices at resonance and monitoring the real-time changes in their resonance frequencies induced by each single molecule adsorption event. We incorporate NEMS into an Orbitrap mass spectrometer and report our progress towards leveraging the single-molecule capabilities of the NEMS to enhance the dynamic range of conventional MS instrumentation and to offer new capabilities for performing deep proteomic analysis of clinically relevant samples. We use the hybrid instrument to deliver E.

Compact and modular system architecture for a nano-resonator-mass spectrometer.

Mass measurements in the mega-to giga-Dalton range are essential for the characterization of natural and synthetic nanoparticles, but very challenging to perform using conventional mass spectrometers. Nano-electro-mechanical system (NEMS) based MS has demonstrated unique capabilities for the analysis of ultra-high mass analytes. Yet, system designs to date included constraints transferred from conventional MS instruments, such as ion guides and high vacuum requirements.

Real-Time Sensing with Multiplexed Optomechanical Resonators.

Nanoelectromechanical resonators have been successfully used for a variety of sensing applications. Their extreme resolution comes from their small size, which strongly limits their capture area. This leads to a long analysis time and the requirement for large sample quantity.

Requirements and attributes of nano-resonator mass spectrometry for the analysis of intact viral particles.

When studying viruses, the most prevalent aspects that come to mind are their structural and functional features, but this leaves in the shadows a quite universal characteristic: their mass. Even if approximations can be derived from size and density measurements, the multi MDa to GDa mass range, featuring a majority of viruses, has so far remained largely unexplored. Recently, nano-electromechanical resonator-based mass spectrometry (NEMS-MS) has demonstrated the ability to measure the mass of intact DNA filled viral capsids in excess of 100 MDa.

The emerging landscape of single-molecule protein sequencing technologies.

Single-cell profiling methods have had a profound impact on the understanding of cellular heterogeneity. While genomes and transcriptomes can be explored at the single-cell level, single-cell profiling of proteomes is not yet established. Here we describe new single-molecule protein sequencing and identification technologies alongside innovations in mass spectrometry that will eventually enable broad sequence coverage in single-cell profiling.

Optomechanical mass spectrometry.

Nanomechanical mass spectrometry has proven to be well suited for the analysis of high mass species such as viruses. Still, the use of one-dimensional devices such as vibrating beams forces a trade-off between analysis time and mass resolution. Complex readout schemes are also required to simultaneously monitor multiple resonance modes, which degrades resolution.

Optomechanical resonating probe for very high frequency sensing of atomic forces.

Atomic force spectroscopy and microscopy are invaluable tools to characterize nanostructures and biological systems. State-of-the-art experiments use resonant driving of mechanical probes, whose frequency reaches MHz in the fastest commercial instruments where cantilevers are driven at nanometer amplitude. Stiffer probes oscillating at tens of picometers provide a better access to short-range interactions, yielding images of molecular bonds, but they are little amenable to high-speed operation.

Enhanced all-optical cavity-tuning using graphene.

All-optical tuning of the resonance of an optical cavity is used to realise optical signal-processing including modulation, switching, and signal-routing. The tuning of optical resonance is dictated by the two primary effects induced by optical absorption: charge-carrier-generation and heat-generation. Since these two effects shift the resonance in opposite directions in a pure silicon-on-insulator (SOI) micro-ring resonator as well as in a graphene-on-SOI system, the efficiency and the dynamic range of all-optical resonance-tuning is limited.

Neutral mass spectrometry of virus capsids above 100 megadaltons with nanomechanical resonators.

Measurement of the mass of particles in the mega- to gigadalton range is challenging with conventional mass spectrometry. Although this mass range appears optimal for nanomechanical resonators, nanomechanical mass spectrometers often suffer from prohibitive sample loss, extended analysis time, or inadequate resolution. We report on a system architecture combining nebulization of the analytes from solution, their efficient transfer and focusing without relying on electromagnetic fields, and the mass measurements of individual particles using nanomechanical resonator arrays.

Single-particle mass spectrometry with arrays of frequency-addressed nanomechanical resonators.

One of the main challenges to overcome to perform nanomechanical mass spectrometry analysis in a practical time frame stems from the size mismatch between the analyte beam and the small nanomechanical detector area. We report here the demonstration of mass spectrometry with arrays of 20 multiplexed nanomechanical resonators; each resonator is designed with a distinct resonance frequency which becomes its individual address. Mass spectra of metallic aggregates in the MDa range are acquired with more than one order of magnitude improvement in analysis time compared to individual resonators.

Frequency fluctuations in silicon nanoresonators.

Frequency stability is key to the performance of nanoresonators. This stability is thought to reach a limit with the resonator's ability to resolve thermally induced vibrations. Although measurements and predictions of resonator stability usually disregard fluctuations in the mechanical frequency response, these fluctuations have recently attracted considerable theoretical interest.

Neutral particle mass spectrometry with nanomechanical systems.

Current approaches to mass spectrometry (MS) require ionization of the analytes of interest. For high-mass species, the resulting charge state distribution can be complex and difficult to interpret correctly. Here, using a setup comprising both conventional time-of-flight MS (TOF-MS) and nano-electromechanical systems-based MS (NEMS-MS) in situ, we show directly that NEMS-MS analysis is insensitive to charge state: the spectrum consists of a single peak whatever the species' charge state, making it significantly clearer than existing MS analysis.

VHF NEMS-CMOS piezoresistive resonators for advanced sensing applications.

This work reports on top-down nanoelectromechanical resonators, which are among the smallest resonators listed in the literature. To overcome the fact that their electromechanical transduction is intrinsically very challenging due to their very high frequency (100 MHz) and ultimate size (each resonator is a 1.2 μm long, 100 nm wide, 20 nm thick silicon beam with 100 nm long and 30 nm wide piezoresistive lateral nanowire gauges), they have been monolithically integrated with an advanced fully depleted SOI CMOS technology.

High frequency top-down junction-less silicon nanowire resonators.

We report here the first realization of top-down silicon nanowires (SiNW) transduced by both junction-less field-effect transistor (FET) and the piezoresistive (PZR) effect. The suspended SiNWs are among the smallest top-down SiNWs reported to date, featuring widths down to ~20 nm. This has been achieved thanks to a 200 mm-wafer-scale, VLSI process fully amenable to monolithic CMOS co-integration.

Modal control of mechanically coupled NEMS arrays for tunable RF filters.

A novel tuning strategy of nanoelectromechanical systems (NEMS)-based filters is proposed based on the modal control of mechanically coupled NEMS arrays. This is done by adjusting separately addressed distributed actuation and detection configurations proportionally to desired modal vectors. This control scheme enhances the global output signal, raising the power handling of the filter on all channels.