Resistive pulse sensing
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Resistive pulse sensing (RPS) is the generic term given for the well-developed commercial technology used to detect, and measure the size of, individual particles in fluid. First invented by Wallace H. Coulter in 1953, the RPS technique is also known as the Coulter Principle. An international standard has been developed for the use of this technique.
The basic principle is shown in Fig. 1, in which individual particles suspended in fluid flow one-at-a-time through a micro- or nanoconstriction. The fluid is weakly conducting, and the obscuration of an electrical sensing current flowing through the fluid by the presence of the particle causes an increase in the measured voltage, in other words, the particle causes a change in the electrical resistance of the nanoconstriction. This is shown schematically in Fig. 2.
The quantitative relationship between the measured change in resistance and particle size was worked out by De Blois and Bean in 1970, where they found the very simple result that the resistance change is proportional to the ratio of particle volume to the effective volume of the nanoconstriction. The dynamic range of an RPS instrument is thus limited at its upper end by the diameter of the nanoconstriction, setting the maximum detectable particle size, and at its lower end by the electrical noise in the sensing circuit, setting the minimum resistance change and thus the minimum particle size that can be detected in a given instrument.
Microfluidic Resistive Pulse Sensing (MRPS)
The original Coulter counter was designed using a special technology to fabricate small pores in glass volumes, but the expense and complexity of fabricating these elements meant they had to be a permanent part of the analytic instrument. This also limited the minimum diameter microconstrictions that could be reliably fabricated, making the RPS technique challenging to use for particles below roughly 1 micron in diameter.
There was therefore significant interest in applying the fabrication techniques developed for microfluidic circuits to RPS sensing. This translation of RPS technology to the microfluidic domain would enable the use of advanced lithographic techniques to fabricate very small nanoconstrictions, extending the minimum detectable particle size into the sub-micron range. This translation would also allow the use of inexpensive cast plastic or elastomer parts for the nanoconstriction component. The use of a disposable element would thus eliminate concerns about sample cross-contamination as well as obviating the need for time-consuming cleaning of the analytic equipment. Significant steps in this direction that were published in the scientific literature were the work by Kasianowicz et al., Saleh and Sohn, and Fraikin et al., which together illustrated methods to fabricate microfluidic versions of the Coulter technology.
- W.H. Coulter, "Means for Counting Particles Suspended in a Fluid", United States Patent 2,656,508
- International Organization for Standardization ISO 13319:2007, https://www.iso.org/standard/42354.html
- R.W. de Blois and C.P. Bean, "Counting and Sizing of Submicron Particles by the Resistive Pulse Technique", Rev. Sci. Instrum. 41, 909 (1970)
- J.J. Kasianowicz et al.. "Characterization of individual polynucleotide molecules using a membrane channel", P. Natl. Acad. Sci. USA 93,13770–13773 (1996)
- O. Saleh and L.L. Sohn, "An artificial nanopore for molecular sensing", Nano Lett. 3, 37–38 (2003)
- J.-L. Fraikin, T. Teesalu, C.M. McKenney, E. Ruoslahti and A.N. Cleland, "A high-throughput label-free nanoparticle analyzer," Nature Nanotechnology 6, 308-313 (2011)