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Solid-state nanopore

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Nanometer-scale hole in an inorganic or two-dimensional membrane, used to sense single molecules

A solid-state nanopore is a hole from about a nanometer to a few hundred nanometers wide in a thin synthetic membrane, or in the tip of a pulled glass capillary, that separates two chambers of salt solution. A voltage across the membrane drives an ionic current through the hole, and a molecule that enters it changes the current for as long as it stays, the principle of resistive pulse sensing. The materials are films of silicon nitride and silicon oxide, single layers of carbon or of molybdenum disulfide, and pulled quartz or borosilicate glass; the holes are made with ion beams, electron beams, high voltage, or by pulling the glass.

Next to a biological nanopore the solid-state pore trades uniformity for durability. It can be made at any diameter, survives heat and harsh chemistry, and can in principle be produced on wafers. It is also noisier and passes DNA too fast to read. No solid-state pore has been reported to read DNA base by base, and the problem has occupied the field since the first pore of 2001.

History

In 2001 Li and colleagues in the laboratories of Golovchenko and Branton described "ion-beam sculpting", a feedback-controlled sputtering system in which low-energy ion beams shape a hole in a silicon nitride membrane, and showed that the resulting pore could register single DNA molecules in aqueous solution.[1] Two years later Storm and colleagues opened a 20 nm pore by electron-beam lithography and etching, oxidized the silicon, and shrank the hole to a single nanometer with the beam of a transmission electron microscope, which fluidizes the oxide so that surface tension closes the hole; when the beam is switched off the material quenches and keeps its shape.[2] The same year the Harvard group demonstrated a "solid-state nanopore microscope" that observed double-stranded DNA and its folding.[3]

The membrane was the next target. Silicon nitride pores were long, about 100 times the spacing of 0.5 nm between bases in single-stranded DNA, as one 2010 paper put it.[4] That year three groups reported pores in graphene membranes, and all three papers recorded DNA passing through them.[5][6] In 2014 Kwok, Briggs and Tabard-Cossa made a single pore down to 2 nm "directly in solution" by applying a voltage across an insulating membrane and watching the leakage current, a method called controlled dielectric breakdown.[7] A review of the field appeared in 2020.[8]

Materials

Membranes for solid-state nanopores
Material Form Notes
Silicon nitride A film 10 to 50 nm thick over a window etched in a silicon wafer The bill of materials of the open MR1 Nanopore Reader lists chips with 10 to 50 nm membranes and 2 to 10 nm pores[9]
Silicon oxide A thermally grown film The beam-shrinking method of 2003[2]
Graphene One to two atoms thick Effective insulating thickness under 1 nm;[5] bare graphene sticks to DNA and clogs[10]
Molybdenum disulfide Monolayer or few layers, under 1 nm Needs no surface treatment to keep DNA from sticking, unlike graphene[11]
Quartz or borosilicate glass A capillary pulled to a point Tips down to 45 nm in 2010; see Glass nanopipette[12]
Cross-sections of four membranes drawn to one scale, a thick one for silicon nitride and two very thin ones for molybdenum disulfide and graphene, beside the spacing of the bases of single-stranded DNA
Membranes drawn to one scale, beside the spacing of the bases in single-stranded DNA (0.32 to 0.52 nm). A schematic.

A silicon nitride chip is a wafer of silicon with a window cut into the back by potassium hydroxide. The etch stops on the {111} planes of the crystal, which leave walls inclined at 54.74° to the surface, so a 10 µm window in the front of a 500 µm wafer needs an opening 717 µm wide behind it.

Cross-section of a silicon wafer with a pit etched from the back, sloping walls at 54.74 degrees, an opening 717 micrometres wide at the back and a 10 micrometre window under a silicon nitride membrane at the front
The geometry of the silicon chip, drawn to scale.

Fabrication

Beams were the first tools. The ion beam of 2001 and the electron beam of 2003 both work by moving material around a hole rather than by cutting a new one, and each can be watched while it works. Focused ion beam milling cuts pores directly; the dielectric method needs only a power supply and the solution the pore will be used in. A low-overhead route is a hand-held Tesla-coil lighter: Bandara and colleagues passed discrete pulses from one through water, in place of electrolyte, across a silicon nitride membrane about 10 nm thick and obtained pores whose λ-DNA signals were "comparable" to those of pores made by other methods.[13] See Nanopore fabrication and Tesla coil lighter pore fabrication.

Wetting

A hole a few nanometers wide does not fill with water by itself. The Laplace pressure of a bubble 5 nm in radius is 2γ/r, 28.8 MPa or 284 atmospheres for water, whose surface tension is 72 mN/m.[a] Smeets and colleagues, measuring pores through the focus of a laser, inferred in 2006 that nanobubbles are the dominant noise source in solid-state nanopores: the current power spectral density of the same pore, measured several times, varied by up to five orders of magnitude.[14] See Nanopore wetting, Nanobubble and Clogging (nanopore).

The founder of Molecular Reality Corporation calls the problem the biggest of what he named "dumb problems": "The biggest, ugliest, dumbest one is: how do you get water through the pore?" He recalls silicon pores drilled by focused ion beam at "about $100 each", most of which broke in the first week or so while the team worked out a wetting protocol, and then one afternoon in which "everything aligned, and we had a beautiful, fully wet, stable 200 nm underpore."[15] See Dumb problems.

Noise

The ionic current through a solid-state pore carries noise at every frequency. Below about 100 Hz it is of the 1/f type, and Smeets and colleagues found that its power scales with the inverse number of charge carriers, as Hooge's relation says, with a parameter of (1.1 ± 0.1) × 10-4. Above about 1 kHz the increase of the power with frequency follows from Johnson noise.[16] At the megahertz bandwidths that fast DNA needs, the largest term is the voltage noise of the amplifier acting across the total capacitance at its input, and the chip is a large part of it. Balan and colleagues, recording through silicon nitride pores under 10 nm thick at up to 1 MHz, cut the chip capacitance to 1 to 5 pF with thick insulating layers and obtained signal-to-noise ratios of 15 to 20 for double-stranded DNA in pores 4 to 8 nm wide, with an input-referred noise of 117 to 150 pA RMS at 1 MHz.[17] The amplifier side of the problem is described in Transimpedance amplifier and Nanopore noise.

Reading DNA

Four obstacles stand between a solid-state pore and a sequencer. Conventional membranes are more than 10 nm thick, and a review of 2026 says that to tell the bases of DNA apart a membrane should ideally be thinner than 0.5 nm. DNA crosses the pore at 1 to tens of bases per microsecond, while a base needs to be in the sensing region for more than 100 µs to be read. Bandwidth is limited to about 1 MHz by the amplifier and the capacitance at its input, and the noise grows with bandwidth. And pores clog, as bare graphene does.[18][19] See Translocation (nanopore) and Speeding bullet problem.

Partial results exist. Feng and colleagues used a viscosity gradient of room-temperature ionic liquids to slow DNA in a monolayer MoS2 pore and statistically detected all four nucleotides from their current signatures, with a signal-to-noise ratio above 10.[20] Osmium bipyridine tags on the pyrimidine bases made the blockades of DNA in a solid-state pore differ with the amount of osmium, enough to gauge the content of T and C in a strand.[21] Dual solid-state pores that pull a strand back and forth mapped the positions of tags on fragments of the Escherichia coli chromosome with a resolution of 150 to 166 base pairs between tags.[22] None of these reads the bases of an unlabeled strand in order. The guide published by Molecular Reality says: "No solid state pore has done it commercially yet."[23] The founder, in a post of March 2026, goes further: "No one has published data demonstrating DNA sequencing with a solid-state pore." He adds that in 2019 two well-informed researchers told him they had heard rumors that a certain group had achieved it, and that "That was a nothingburger."[24]

Other uses

Most results from solid-state pores are not about sequencing. Yusko and colleagues used the zeptoliter sensing volume of lipid-coated pores to estimate the approximate shape, volume, charge, rotational diffusion coefficient and dipole moment of single proteins in one measurement.[25] Pores several hundred nanometers wide count and size nanoparticles and cells, as in the Coulter principle. Arima and colleagues detected single viruses with them in 2018, and in 2021 Taniguchi and colleagues combined a nanopore with machine learning to detect coronaviruses without extracting RNA; see Virus detection with nanopores.[26][27] Pores whose size can be changed during a measurement are on the market from Izon Science, which builds them on a stretchable membrane; see Tunable resistive pulse sensing.[28]

At Molecular Reality

The company's guide describes solid-state pores as "machined chips, usually holes in a thin silicon nitride membrane" that "can survive heat, harsh chemistry, and being tuned to different sizes", and the way it makes them as "beams of ions, a kind of atomic scale sandblasting, or by dielectric breakdown, where a voltage punches the hole for you." Of the result it says: "A hole this small is an object you build, then photograph, then hope."[23] The pore on its Live molecular stream is a laser-drilled hole listed in the lab records as 200 µm wide, and the guide concedes that "the pores we stream today are larger than a nanometer".[29][23]

Molecular Reality's own idea is a mechanical nanopore whose opening is set by sliding one membrane across another, in the hope of slowing DNA enough to read it. Of that, the guide says: "That is the plan, and I flag it as a plan."[23] The founder's name for reading labeled bases with a solid-state pore is the Holey Grail, with an asterisk for the labels.[30] In the company's game-like member system, the quest "Sequence DNA with an ss-nanopore" is worth 9,900,000 experience points.[31]

See also

Notes

  1. ^ 2 × 0.072 N/m / 5 × 10-9 m = 2.88 × 107 Pa, which is 284 times 101,325 Pa.

References

  1. ^ Li, J.; et al. (2001). "Ion-beam sculpting at nanometre length scales". Nature 412 (6843): 166-169. doi:10.1038/35084037. PMID 11449268.
  2. ^ a b Storm, A. J.; et al. (2003). "Fabrication of solid-state nanopores with single-nanometre precision". Nature Materials 2 (8): 537-540. doi:10.1038/nmat941. PMID 12858166.
  3. ^ Li, J.; et al. (2003). "DNA molecules and configurations in a solid-state nanopore microscope". Nature Materials 2 (9): 611-615. doi:10.1038/nmat965. PMID 12942073.
  4. ^ Schneider, G. F.; et al. (2010). "DNA translocation through graphene nanopores". Nano Letters 10 (8): 3163-3167. doi:10.1021/nl102069z. PMID 20608744.
  5. ^ a b Garaj, S.; et al. (2010). "Graphene as a subnanometre trans-electrode membrane". Nature 467 (7312): 190-193. doi:10.1038/nature09379. PMID 20720538.
  6. ^ Merchant, C. A.; et al. (2010). "DNA translocation through graphene nanopores". Nano Letters 10 (8): 2915-2921. doi:10.1021/nl101046t. PMID 20698604.
  7. ^ Kwok, H.; Briggs, K.; Tabard-Cossa, V. (2014). "Nanopore fabrication by controlled dielectric breakdown". PLoS ONE 9 (3): e92880. doi:10.1371/journal.pone.0092880. PMID 24658537.
  8. ^ Xue, L.; et al. (2020). "Solid-state nanopore sensors". Nature Reviews Materials 5 (12): 931-951. doi:10.1038/s41578-020-0229-6.
  9. ^ "MR1 Nanopore Reader bill of materials". GitHub. Molecular Reality Corporation. October 2026.
  10. ^ Schneider, G. F.; et al. (2013). "Tailoring the hydrophobicity of graphene for its use as nanopores for DNA translocation". Nature Communications 4: 2619. doi:10.1038/ncomms3619.
  11. ^ Liu, K.; et al. (2014). "Atomically thin molybdenum disulfide nanopores with high sensitivity for DNA translocation". ACS Nano 8 (3): 2504-2511. doi:10.1021/nn406102h. PMID 24547924.
  12. ^ Steinbock, L. J.; et al. (2010). "Detecting DNA folding with nanocapillaries". Nano Letters 10 (7): 2493-2497. doi:10.1021/nl100997s. PMID 20515038.
  13. ^ Bandara, Y. M. N. D. Y.; et al. (2019). "Push-button method to create nanopores using a Tesla-coil". ACS Omega 4 (1): 226-230. doi:10.1021/acsomega.8b02660.
  14. ^ Smeets, R. M. M.; et al. (2006). "Nanobubbles in solid-state nanopores". Physical Review Letters 97 (8): 088101. doi:10.1103/PhysRevLett.97.088101.
  15. ^ Kemmishtree (March 29, 2026). "Focused Ion Beam pore". EQBio-OS.
  16. ^ Smeets, R. M. M.; Keyser, U. F.; Dekker, N. H.; Dekker, C. (2008). "Noise in solid-state nanopores". Proceedings of the National Academy of Sciences 105 (2): 417-421. doi:10.1073/pnas.0705349105.
  17. ^ Balan, A.; et al. (2014). "Improving signal-to-noise performance for DNA translocation in solid-state nanopores at MHz bandwidths". Nano Letters 14 (12): 7215-7220. doi:10.1021/nl504345y.
  18. ^ Chen, X.; et al. (2026). "Addressing the challenges of solid-state nanopores: strategies for performance enhancement". International Journal of Molecular Sciences 27 (6): 2536. doi:10.3390/ijms27062536.
  19. ^ Deamer, D.; Akeson, M.; Branton, D. (2016). "Three decades of nanopore sequencing". Nature Biotechnology 34 (5): 518-524. doi:10.1038/nbt.3423. PMID 27153285.
  20. ^ Feng, J.; et al. (2015). "Identification of single nucleotides in MoS2 nanopores". Nature Nanotechnology 10 (12): 1070-1076. doi:10.1038/nnano.2015.219. PMID 26389660.
  21. ^ Henley, R. Y.; et al. (2015). "Osmium-based pyrimidine contrast tags for enhanced nanopore-based DNA base discrimination". PLOS ONE 10 (12): e0142155. doi:10.1371/journal.pone.0142155. PMID 26657869.
  22. ^ Rand, A.; et al. (2022). "Electronic mapping of a bacterial genome with dual solid-state nanopores and active single-molecule control". ACS Nano 16 (4): 5258-5273. doi:10.1021/acsnano.1c09575. PMID 35302746.
  23. ^ a b c d "Keltar's Field Guide to Molecular Reality". Molecular Reality Corporation. August 2026.
  24. ^ Kemmishtree (March 28, 2026). "2022 sci-tech overview". EQBio-OS.
  25. ^ Yusko, E. C.; et al. (2017). "Real-time shape approximation and fingerprinting of single proteins using a nanopore". Nature Nanotechnology 12 (4): 360-367. doi:10.1038/nnano.2016.267. PMID 27992411.
  26. ^ Arima, A.; et al. (2018). "Selective detections of single-viruses using solid-state nanopores". Scientific Reports 8: 16305. doi:10.1038/s41598-018-34665-4.
  27. ^ Taniguchi, M.; et al. (2021). "Combining machine learning and nanopore construction creates an artificial intelligence nanopore for coronavirus detection". Nature Communications 12: 3726. doi:10.1038/s41467-021-24001-2.
  28. ^ Lenora Ashgrove (October 8, 2026). "Can a Hole That Slides Read a Molecule?" Signal & Noise.
  29. ^ "Streams". Molecular Reality Corporation. 2026.
  30. ^ Kemmishtree (March 29, 2026). "Magic with labels". EQBio-OS.
  31. ^ "Quest board". EQBio-OS. Molecular Reality Corporation. October 2026.
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