Resistive pulse sensing

Resistive pulse sensing is the measurement of single particles, cells or molecules suspended in an electrolyte by the brief change in electric current as each one passes through a small pore or channel. A particle in the aperture displaces conducting liquid, the resistance of the aperture rises, and the current dips for as long as the particle is inside. Each dip is one particle, the depth of the dip tracks its volume, the width of the dip is its transit time, and the number of dips a second tracks the concentration. The name is the nanopore literature's term for the Coulter principle; the title of the 1970 paper by DeBlois and Bean that took the method below a micrometer already speaks of "the resistive pulse technique". It covers the same measurement across five orders of magnitude in size, from the 100 µm apertures of a Coulter counter to the 1 nm channels that read single polymers.^[1][2]

Some particles raise the current instead of lowering it, which is called a conductive pulse. DNA in a silicon nitride pore does so below about 0.4 M potassium chloride and lowers the current above it.^[3]

For a particle much smaller than the aperture, the fractional change in resistance is proportional to the volume of the particle divided by the volume of the sensing zone. For a sphere of diameter d in an aperture of diameter D and effective length L_eff, $\Delta R/R\approx d^3/(D^2{L}_{\text{eff}})$.^[4] The cube is the whole difficulty. Beckman Coulter gives the working range of one aperture as 2% to 60% of its diameter, a 30-fold range of sizes and a 27,000-fold range of volumes. At the lower limit, in an aperture with the proportions of the first commercial counter, a particle changes the resistance by about five parts per million.^[a] Below that limit the pulse approaches the noise, so smaller particles need smaller apertures.^[1] The sources and scaling of the noise are described in Nanopore noise.

In a nanopore the particle is a molecule and the geometry changes. The aperture can be shorter than the particle, and the access regions at its two mouths carry a large part of the total resistance, so the sensing zone reaches beyond the pore (Access resistance). The fractional signal is correspondingly large: double-stranded DNA 2.2 nm wide in a pore 5 nm wide blocks about 17% of the current once the access resistance is counted, and 19% from the areas alone (see Current blockade), against a few parts per million for the smallest particle a Coulter aperture can size.^[5]

Two particles in the aperture at once give one pulse of the wrong size, a coincidence. Beckman Coulter treats losses of up to 10% as correctable by calculation, and the first remedy is dilution.^[1]

In the middle of the table the instruments are small. A microfluidic analyzer reported in 2011 had a throughput of 500,000 particles a second and sized and titered bacteriophage T7 from about a microliter of sample. In mouse blood plasma it found, unexpectedly, "a large background of naturally occurring nanoparticles" whose sizes followed a power law.^[7] Spectradyne sells instruments built on this method, with a disposable cartridge that holds the constriction.^[12] A pore of carbon nanotube set in epoxy and mounted on PDMS cut the background noise by a factor of more than 20 compared with a silicon nitride support, enough to measure both the size and the transit time, and so the charge, of individual nanoparticles.^[9]

A pore of fixed size works over a limited range, and a membrane whose pore can be changed during a run works over more. In 2007 Sowerby, Broom and Petersen described "dynamically resizable nanometre-scale apertures for molecular sensing", an opening in an elastomeric membrane that changes size when the membrane is stretched, and in the same year Huh and colleagues made nanochannels in silicone rubber whose width was set by strain.^[13][14] The method was then developed as tunable resistive pulse sensing, in which a pore in an elastomer is stretched to change its size and is calibrated against particles of known size.^[15][16] Izon Science of Christchurch sells instruments based on it. Its Exoid, announced in March 2021, replaced the qNano.^[17]

It has been applied to extracellular vesicles. Pores differ in diameter, and the smallest vesicle each can detect differs with it. In a study on a standard urine sample the minimum detected diameter was 128 ± 19 nm in 102 daily measurements, and the measured vesicle concentration ranged from 1.4 × 10⁸ to 1.8 × 10¹⁰ per milliliter.^[8]

Molecular Reality Corporation describes its juxtapore as "a pore formed by two surfaces sliding alongside each other, their edges close enough to form the sensing gap."^[18] An adjustable aperture is older than the company, and the elastomeric version has been on sale for years. What the juxtapore changes is the mechanism: the membranes of the stack described in US patent 10,908,144 are rigid films, and the aperture is set by sliding one over another, where the older devices stretch something soft.^[19] None of the company's evidence for sliding occlusion has been through peer review.

Blood counting is the oldest. The impedance principle still counts cells in automated hematology analyzers, which measure cells by electrical impedance, by optical analysis, or by both.^[20] Immunoassays use the pulse to read a change of size. Saleh and Sohn coated latex colloids with streptavidin and measured the increase in their diameter as antibodies bound, without labels.^[6] Viruses can be sized and typed. A solid-state pore with electro-osmotic flow at its mouth identified the type of influenza virus with 68% accuracy one virion at a time, and above 95% when the signals of more than 20 virions were combined.^[10] Later work applied machine learning to the signals of coronaviruses (Virus detection with nanopores).^[21]

A pore can also measure the same particle many times. In 2015 a nanopipette with programmable voltage reversal sent one polystyrene particle back through the orifice thousands of times at more than 100 measurements a second, which narrowed the uncertainty of its mean size (see Ping-pong sensing).^[22]

The pore on the company's live molecular stream is at the Coulter end of the scale: a laser-drilled hole 200 µm across, inside the range of standard Coulter apertures. The provisions list for the stream gives its first sample as tap water, entered as a "Baseline conductivity standard".^[23] The company's guide says why: at the larger pores of today, ketchup, salsa and tap water "can be watched at the scale of cells and particles, counting what passes, the way Coulter did seventy years ago", while at the nanometer scale "they would clog the doorway instantly".^[18] A post of March 29, 2026 on the company's member site makes the same point about the instruments: "Coulter Counters are pore-based devices, but in the era of commercialized nanopore sequencing, it's easy to forget that the only serious difference is size."^[24]

• Coulter counter
• Wallace H. Coulter
• Current blockade
• Polystyrene bead
• Flow cytometry
• Nanopore

• Graham, M. D. (2003). "The Coulter principle: Foundation of an industry". JALA: Journal of the Association for Laboratory Automation 8 (6): 72-81. doi:10.1016/S1535-5535-03-00023-6.