Tunable resistive pulse sensing

Tunable resistive pulse sensing (TRPS) counts and sizes particles one at a time with a pore that can be widened or narrowed by hand. The pore is a hole in an elastomer membrane, polyurethane in the commercial instruments, held in a frame that stretches it. Stretch the membrane and the hole opens; release it and the hole closes. A 2018 perspective gives the working range as "tens of nanometers through to micrometers".^[1] Izon Science of New Zealand has sold instruments built on it since 2009, and it remains the one commercial precedent for a pore that changes size during use.

Sowerby, Broom and Petersen described the pore in 2007 in a paper titled "Dynamically resizable nanometre-scale apertures for molecular sensing": a hole made through a thick elastomeric membrane and opened and closed by stretching the membrane.^[2] The first instruments left Izon in September 2009, and in January 2010 the company reported that it had "recently released" version 1.0 of the qNano.^[3] A review of 2011 noted that the technique of resistive pulse sensing had been outlined and commercialized more than fifty years earlier, in the Coulter counter, and that nanoscale fabrication had revived it.^[4]

Two cells of salt solution are joined only by the pore. A voltage across it drives an ionic current, and a particle that enters the pore pushes conducting liquid out of the way, so the current dips until the particle leaves. This is the Coulter principle, and TRPS uses it unchanged.

The dip is the volume of the particle measured against the volume of the pore. A sphere 100 nm across displaces about 520 zeptoliters of solution. For a particle much smaller than a cylindrical pore of diameter D and length L, the fractional change in resistance is about d³/(D²L), the result Maxwell derived and DeBlois and Bean refined in 1970.^[5] Two consequences follow. A particle twice as wide gives eight times the dip, so a sample spread over a factor of two in size spreads its dips over a factor of eight. And a narrower pore gives a bigger dip for the same particle: at the same length, halving D quadruples it. The pore of a TRPS instrument is a cone and not a cylinder, and its narrowest region does the counting, so the cube law is a guide and not a formula.

A fixed pore handles a band of sizes. A particle wider than the pore cannot enter, and a particle much narrower than it gives a dip below the noise. Stretching moves the band. Kozak and colleagues reported in 2012 that tuning the pore by stretching lets a larger range of sample sizes be analyzed, improves the sensitivity, and changes the forces on the particles.^[6] Those forces are the electrophoretic pull of the voltage and the flow driven by a pressure across the pore, and both move particles through. Because the part of the motion due to the voltage depends on the charge of the particle, the pulse can give a charge as well as a size. The same paper took both from single pulses in a mixture of two particle sets that differed in size and charge.

The method does not measure diameter directly. Vogel and colleagues found in 2011 that the change in resistance is linear in the volume of the particle, as Maxwell had suggested, and turned dips into diameters by first running carboxylated polystyrene beads of known sizes through the same membrane at the same stretch. The sizes they then calculated for plastic particles and for adenovirus agreed with transmission electron microscopy and light scattering.^[7] A new stretch needs a new calibration.

Counting works differently. In 2012 Roberts and colleagues showed with polystyrene particles from 210 to 710 nm that the number of events per second rises in proportion to both the pressure and the concentration, whatever the type and size of the particle. They counted baculovirus occlusion bodies, about 1 µm across, and the marine cyanobacterium Prochlorococcus, about 600 nm, and found concentrations within 17% of a microscope count and within 6% of a flow cytometer's, respectively.^[8] Their technique, scanning ion occlusion sensing, had an earlier form called scanning ion occlusion spectroscopy.^[9]

Most use is on extracellular vesicles, the membrane-bound particles cells release, a field that Willmott called "particularly popular" for the method. It is also used for liposomes, viruses and in on-bead assays.^[1] The same perspective asks for more rigor, in the statistics, in the physical models of the pulse and in the treatment of uncertainty.

The weak point is the pore itself. Because the pores are made in a molded elastomer, two nominally identical pores do not measure alike; the figures are in Izon Science. A 2011 review counted size-tunable pores among three newer designs of pore sensor, the others being pores in series and in parallel, that cover particles from 10 to 900 nm with better sensitivity than a single fixed pore.^[4]

Stretching is one of three routes to an adjustable pore described in Mechanical nanopore. The sliding design of Molecular Reality Corporation, a juxtapore made of rigid membranes that move over one another, uses another. A science-magazine report on the design, published October 8, 2026, says that tunable pores already exist and names Izon.^[10] Izon's newest instrument, the Pulsoid of June 2026, goes the other way: it is built on a silicon chip with a "fixed pore geometry".^[11]

• Sliding occlusion
• Spectradyne
• Polystyrene bead
• Flow cytometry
• Zeptoliter