Multiple-mode mass-sensing

Towards nanoscale mass tomography in solution

Measuring the physical properties -e.g. mass, density or shape- of nanoscale objects is challenging. Such capabilities are particularly important for nanoparticles in biological fluids like viruses, extracellular vesicles or proteins, since most often their functionality depends on their shape, size, content or density. It is extremely challenging to resolve these particles by optical approaches due to wavelength-dependent diffraction limit.

Recently, we have developed suspended nanochannel resonators (SNR) for weighing single nanoparticles down to 10 nm in solution. Although SNR is a powerful tool for analyzing nanoparticle populations in solution due to its high precision and wide dynamic range for concentration and mass, it only measures a single physical property of a particle. Weather a particle of a measured mass is small and dense or larger but less dense cannot be determined. Furthermore, particles with the same mass can show differences in terms of their shapes or the distribution of the mass within the particle. 

Here we developed a technique to simultaneously oscillate multiple vibrational modes of an SNR and monitor its mode frequencies with high precision as nanoparticles quickly flow through the integrated fluidic channel. As the particles flow through the channel each mode frequency responds differently to the particle mass and position along the resonator (see animation). We exploited our system to monitor multiple nanoparticles with different masses that are in close proximity to each other as they flow through the channel. We monitored the relative positions of the masses dynamically during their quick transition (~100 ms) through the SNR. Using the first four vibrational modes, we could attain a position resolution of about 150 nm. We expect that if we could extend our system to eight modes with improved noise performance, we could achieve a position resolution of about four nanometers. We envision such a resolution could enable high speed mass tomography of nanoparticles in solution as they flow trough a microfluidic channel. 

The ability to resolve nanoparticle pairs in close proximity in a resonator suggests the possibility of observing bimodal mass distributions within a population of single particles, or resolving high-aspect-ratio shapes versus more spherical shapes in solution. In addition, to be able to monitor the dynamic changes in the mass distributions could be used for online monitoring of the assembly of engineered nanoparticles such as DNA origami or nanoparticles designed for nanomedicine. The same approach, when applied to larger resonators that can sustain bacteria or mammalian cells, could ultimately be used to obtain high-throughput mass tomography of single living cells.

Our technique comprises two key innovations – an easily-scalable array of phase-locked loops (PLLs) and a method that precisely controls the behavior of each PLL when it is placed in feedback with a resonator mode. Although PLLs are well-understood, the dynamics of a resonator in feedback with a PLL is quite different than the dynamics of the PLL alone.  In this work, we explain these dynamics and employ them to engineer the resonator behavior in a number of desirable ways – controllable bandwidth, flat response, and sharp roll-off. Details of this technique can be found in the article below and further implementation details will be given here.  

Selim Olcum§, Nathan Cermak§ et.al., High-speed multiple-mode mass-sensing resolves dynamic nanoscale mass distributions.
Nature Communications, 2015.   Manuscript (1.4 MB)  Supp. Info (7.4 MB) § Contributed equally to this work.
See MIT News for the news article.