High-Speed Multipass Coulter Counter with Ultrahigh Resolution

Coulter counters measure the size of particles in solution by passing them through an orifice and measuring a resistive pulse, i.e., a drop in the ionic current flowing between two electrodes placed on either side of the orifice. The magnitude of the pulse gives information on the size of the particle; however, resolution is limited by variability in the path of the translocation, due to the Brownian motion of the particle. We present a simple yet powerful modified Coulter counter that uses programmable data acquisition hardware to switch the voltage after sensing the resistive pulse of a nanoparticle passing through the orifice of a nanopipet. Switching the voltage reverses the direction of the driving force on the particle and, when this detect-switch cycle is repeated, allows us to pass an individual nanoparticle through the orifice thousands of times. By measuring individual particles more than 100 times per second we rapidly determine the distribution of the resistive pulses for each particle, which allows us to accurately determine the mean pulse amplitude and deliver considerably improved size resolution over a conventional Coulter counter. We show that single polystyrene nanoparticles can be shuttled back and forth and monitored for minutes, leading to a precisely determined mean blocking current equating to sub-angstrom size resolution.