Rapid and high-precision sizing of single particles using parallel suspended microchannel resonator arrays and deconvolution

Abstract

Measuring the size of micron-scale particles plays a central role in the biological sciences and in a wide range of industrial processes. A variety of size parameters, such as particle diameter, volume, and mass, can be measured using electrical and optical techniques. Suspended microchannel resonators (SMRs) are microfluidic devices that directly measure particle mass by detecting a shift in resonance frequency as particles flow through a resonating microcantilever beam. While these devices offer high precision for sizing particles by mass, throughput is fundamentally limited by the small dimensions of the resonator and the limited bandwidth with which changes in resonance frequency can be tracked. Here, we introduce two complementary technical advancements that vastly increase the throughput of SMRs. First, we describe a deconvolution-based approach for extracting mass measurements from resonance frequency data, which allows an SMR to accurately measure a particle's mass approximately 16-fold faster than previously possible, increasing throughput from 120 particles/min to 2000 particles/min for our devices. Second, we describe the design and operation of new devices containing up to 16 SMRs connected fluidically in parallel and operated simultaneously on the same chip, increasing throughput to approximately 6800 particles/min without significantly degrading precision. Finally, we estimate that future systems designed to combine both of these techniques could increase throughput by nearly 200-fold compared to previously described SMR devices, with throughput potentially as high as 24 000 particles/min. We envision that increasing the throughput of SMRs will broaden the range of applications for which mass-based particle sizing can be employed.

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“…This level of throughput is likely compatible with current clinical pathology workflows. Further, we estimate that the time-per-sample could be significantly reduced: as we have shown previously (20), using more concentrated cell samples, the SMR can achieve mass measurement throughput reaching thousands of cells per minute, potentially reducing the required SMR instrument time per sample by several fold.…”

“…Recently, high-throughput single-cell mass measurements have been enabled by the parallel SMR array (Fig. 1C), a microfluidic device containing sixteen SMRs connected fluidically in parallel and operated simultaneously on the same microfluidic chip (20). By operating many sensors simultaneously, a population of cells can be weighed with maximum throughput of thousands of cells per minute.…”

“…SMR mass measurements were performed using parallel SMR arrays, as described previously (20). Briefly, single cells in suspension flow through a micromechanical resonator with an embedded fluidic channel, generating a shift in resonance frequency proportional to the cell's mass.…”

“…The sensors are calibrated by measuring monodisperse polystyrene beads of known mass. The measurements described here were performed using a parallel SMR array, in which twelve sensors are connected fluidically in parallel and operated simultaneously for increased throughput (20). Before measurement, the fluidic channels were passivated with poly-L-lysine-grafted poly(ethylene glycol).…”

“…We used a similar approach to estimate the sample throughput of the parallel SMR array. Based on a previous study, these devices can measure cell mass at a maximum throughput of 6800 particles/minute when optimized for speed (20). For our order-of-magnitude throughput calculations we used a more conservative estimate of 1000 particles/minute, since most tumor cell samples are sparse and throughput is lower when measuring these generally lower-concentration samples.…”