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Nanopore fabrication

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From Molecupedia, the encyclopedia of very small things
Methods of making single pores of nanometre size in thin membranes
For pores made of proteins, which assemble themselves, see Biological nanopore.

Nanopore fabrication is the making of single holes, from about one nanometre to a few hundred nanometres across, in membranes thin enough for the hole to serve as an electrical sensor. Protein pores assemble themselves in a membrane; every other kind of nanopore has to be cut, drilled, etched, broken or pulled into shape. The main methods are milling with focused beams of ions or electrons, which places a pore exactly but needs an electron microscope or an ion-beam instrument; controlled dielectric breakdown, in which a voltage applied in salt water breaks a pore through the membrane; chemical etching along the damage tracks of heavy ions or the crystal planes of silicon; and pulling heated glass capillaries to a fine tip.

Each method trades control of size and position against cost and speed, and none makes two pores exactly alike. Molecular Reality Corporation's public guide describes the craft in two sentences: "We make them with beams of ions, a kind of atomic scale sandblasting, or by dielectric breakdown, where a voltage punches the hole for you. Then we photograph the result under an electron microscope to prove the hole is really there."[1]

Membranes

Main article: Silicon nitride membrane
Cross-section of a silicon chip with a pyramid-shaped pit etched from the back, its sloping walls at 54.74 degrees, ending at a thin membrane window on the front
Etching from the back of a silicon wafer 500 µm thick. The walls of the pit follow the crystal's planes at 54.74°, so a membrane window 10 µm wide on the front needs an opening 717 µm wide on the back.

Most solid-state pores are made in a film of silicon nitride, deposited by low-pressure chemical vapour deposition on a silicon wafer to a thickness of 10 to 50 nm, often with a low-stress, silicon-rich composition. The silicon under a small area is then etched away from the back to leave a free-standing window of film. Hot potassium hydroxide etches silicon along its crystal planes and stops at the slow {111} planes, which meet the wafer surface at 54.74°, the angle whose cosine is 1/√3. The pit is a truncated pyramid, and its geometry fixes the opening needed on the back: for a window 10 µm wide in a wafer 500 µm thick it is 10 µm plus twice 500 µm × cot 54.74°, or 717 µm. The film can be thinned further at the pore site, by reactive-ion etching through a mask or with a focused laser.[2]

The chip matters as much as the hole. The silicon frame conducts, and a membrane on it forms a capacitor with the solutions on both sides; the capacitance converts amplifier voltage noise into current noise at high frequencies. Chips on glass, with the membrane supported by an insulator, brought the capacitance below 1 pF in 2015.[3] Sheets one atom thick, such as graphene and molybdenum disulfide, are transferred onto a supporting window and drilled in place; see Graphene nanopore and Molybdenum disulfide nanopore.

Beam methods

Ion beams

Main article: Focused ion beam

The first solid-state pore to detect DNA was made in 2001 at Harvard by ion-beam sculpting. A beam of low-energy ions, aimed at a silicon nitride membrane with a larger hole, did not simply widen it: in the right conditions the ions drove material across the surface and closed the hole, and the rate at which ions passed through the shrinking opening served as feedback to stop it at molecular size.[4] A focused beam of gallium ions mills pores directly, usually tens of nanometres across, and in 2006 a focused ion beam followed by an electron beam produced symmetric pores smaller than 5 nm.[5] The lighter ions of a scanning helium ion microscope cut pores below 4 nm, quickly and with noise comparable to that of pores drilled by electrons.[6]

Electron beams

The focused beam of a transmission electron microscope can both drill a pore and watch it form. In 2003 Cees Dekker's group at Delft opened pores about 20 nm wide in silicon by lithography and etching, oxidized them, and then shrank them under a high-energy electron beam, which fluidized the silicon oxide so that surface tension closed the hole; when the beam was switched off the oxide set in its new shape. The method gave single-nanometre control with direct visual feedback.[7] Drilling silicon nitride directly with a converged electron beam became the standard laboratory route, and arrays of pores of uniform size were made this way by 2006.[8] The smallest pores made this way, 0.8 to 2 nm in membranes thinned to 5 to 8 nm, distinguished short DNA strands of single repeated bases in 2013.[9] Lithography with a single shot of an electron beam, followed by reactive-ion etching, makes whole arrays at once, with pores as small as 16 nm in silicon nitride and graphene.[10]

Breakdown in solution

Main article: Controlled dielectric breakdown

In 2014 a group at the University of Ottawa showed that the beam can be skipped. A voltage of several volts across a membrane in salt solution creates a field strong enough to break down the insulator; the leakage current through the membrane is watched, and the voltage is cut the moment the current jumps. What remains is a single pore, which can be as small as 2 nm.[11] The pore forms already wet, in the solution where it will be used. Further pulses of high field enlarge it and lower its noise, and a published protocol of 2019 reports yields above 85% in less than an hour with instruments that a non-specialist can build.[12][13] The position of the pore is random, which matters little for one pore and a great deal for arrays. A focused laser can fix it: light etches the membrane locally, either opening the pore itself or thinning the film so that the breakdown happens there.[14][2]

Main article: Tesla coil lighter pore fabrication

The cheapest version uses a handheld Tesla-coil lighter, which costs about $20. In 2019 a group at the University of Rhode Island used one to make ion-conducting pores through silicon nitride about 10 nm thick. It replaced the electrolyte with water, to raise the resistance of the circuit, and applied the voltage in discrete bursts instead of continuously; the resulting pores passed lambda DNA with signals comparable to those of pores made by other methods.[15] Molecular Reality tried the method for a night or two. Its founder's post about it, from March 2026, begins: "Yes, we actually tried this." It adds that one advantage over a 9-volt battery "is that it might open up making pores through membranes too thick for that approach", that "Results were messy", and that "we may or may not have made pores, but it's worth trying again."[16] The company also built the Burnerphone, a compact research unit that used controlled dielectric breakdown, and later withdrew it from commercial sale.[17]

Chemical etching

Heavy ions fired through a plastic film leave a narrow trail of damaged polymer, and an alkaline etch dissolves the trail much faster than the undamaged film, opening a pore. The method dates from the early 1960s; Robert Fleischer, P. Buford Price and Robert Walker reviewed it in 1965.[18] Track-etched membranes with many pores became filters, and films hit by a single ion give single pores: DeBlois and Bean sized submicron particles with them in 1970, and etching from one side gives the conical pores used to study ion current rectification.[19][20]

Crystal planes do the measuring in silicon. The same potassium hydroxide etch that opens membrane windows also cuts inverted pyramids through thin silicon, and their tips can be made into pores. A group at Brown University stopped such an etch the moment current began to flow through the tip, and a group at KTH in Stockholm shrank pyramidal pores by thermal oxidation, a self-limiting process that reached openings as small as 8 nm.[21][22] In a single layer of molybdenum disulfide an electrochemical reaction starting at a defect removes atoms one at a time, and step-like rises in the ionic current report the size of the growing pore as it opens.[23]

Glass

Main article: Glass nanopipette

A glass capillary heated by a laser and pulled apart thins to a tip whose opening can be tens of nanometres across. In 2010 a group at Cambridge pulled capillaries to openings as small as 45 nm and detected the folding of single DNA molecules through them.[24] Exposure to the electron beam of a scanning electron microscope shrinks the opening further, to 14 nm in a study of 2013, which found that the shrunken glass pores gave smaller signals than silicon nitride pores but lower noise and a better signal-to-noise ratio.[25] Pulled glass needs no clean room.

Reported sizes

Methods of making solid-state pores, with sizes reported in the papers cited above
Method Membrane Smallest size reported Position of pore
Ion-beam sculpting Silicon nitride Molecular scale Set by the starting hole
Focused gallium ion beam, then electron beam Silicon nitride Below 5 nm Chosen
Helium ion milling Silicon nitride Below 4 nm Chosen
Electron-beam shrinking of oxidized silicon Silicon oxide Single nanometres Chosen
Electron-beam lithography and reactive-ion etching Silicon nitride, graphene 16 nm Chosen, many at once
Controlled dielectric breakdown Silicon nitride 2 nm Random
Laser etching with breakdown Silicon nitride 1 to 2 nm Chosen
Oxidation of pyramidal pits Silicon 8 nm Set by lithography
Electrochemical reaction Molybdenum disulfide Below 1 nm precision At defects
Laser pulling and electron shrinking Glass 14 nm Tip of the capillary

Moving and stacked pores

A square silicon chip with a four-by-four grid of windows held in a machined aluminium carrier with four screw holes
A Molecular Aquarium chip in its machined carrier, with a four-by-four grid of windows

A pore whose shape can change after it is made needs a different kind of fabrication: two or more membranes, each with its own pores, aligned and stacked so that they can move. US patent 10,908,144, filed in 2018 and granted in 2021, describes "stacks of coaligned nanopores", their fabrication and their uses: membranes stacked directly on one another, one of which is moved sideways to change the shape of the passage through them.[26] Its inventor is the founder of Molecular Reality Corporation, which calls the resulting adjustable gap a juxtapore and the principle sliding occlusion; see Patent US 10,908,144.

Early sliding-occlusion work at the company used pores it bought. Around 2018, when it was still demonpore, inc., it used a handful of silicon pores drilled by focused ion beam at about $100 each, under a top blade that slid across them. Most broke in the first week or so of searching for a way to wet them; on the best afternoon the team recorded "a beautiful, fully wet, stable 200 nm underpore", with the current moving up and down as the blade slid across it.[27] In 2020 it had arrays of pores made by a microfabrication company for its Molecular Aquarium, "using a modified DRIE process", the deep reactive-ion etching that Robert Bosch GmbH patented in the 1990s, in which short steps of fluorine etching alternate with steps that coat the side walls with polymer.[28][29] The pores are all under 10 µm, in membranes thin enough to glow red when lit from below, and each array was designed to slide across a partner array of dozens of pores so that only one pair lined up at a time.[28]

The pore in the company's live molecular stream is simpler: a hole drilled by laser, listed in its records as 200 µm across, within the range of the apertures of standard Coulter counters.[30] See 200-micron laser-drilled pore.

See also

References

  1. ^ "Keltar's Field Guide to Molecular Reality". Molecular Reality Corporation. August 2026.
  2. ^ a b Yamazaki, H.; Hu, R.; Zhao, Q.; Wanunu, M. (2018). "Photothermally assisted thinning of silicon nitride membranes for ultrathin asymmetric nanopores". ACS Nano 12 (12): 12472-12481. doi:10.1021/acsnano.8b06805.
  3. ^ Balan, A.; Chien, C.-C.; Engelke, R.; Drndić, M. (2015). "Suspended solid-state membranes on glass chips with sub 1-pF capacitance for biomolecule sensing applications". Scientific Reports 5: 17775. doi:10.1038/srep17775.
  4. ^ Li, J.; Stein, D.; McMullan, C.; Branton, D.; Aziz, M. J.; Golovchenko, J. A. (2001). "Ion-beam sculpting at nanometre length scales". Nature 412 (6843): 166-169. doi:10.1038/35084037.
  5. ^ Lo, C. J.; Aref, T.; Bezryadin, A. (2006). "Fabrication of symmetric sub-5 nm nanopores using focused ion and electron beams". Nanotechnology 17 (13): 3264-3267. doi:10.1088/0957-4484/17/13/031.
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  8. ^ Kim, M. J.; Wanunu, M.; Bell, D. C.; Meller, A. (2006). "Rapid fabrication of uniformly sized nanopores and nanopore arrays for parallel DNA analysis". Advanced Materials 18 (23): 3149-3153. doi:10.1002/adma.200601191.
  9. ^ Venta, K.; et al. (2013). "Differentiation of short, single-stranded DNA homopolymers in solid-state nanopores". ACS Nano 7 (5): 4629-4636. doi:10.1021/nn4014388.
  10. ^ Verschueren, D. V.; Yang, W.; Dekker, C. (2018). "Lithography-based fabrication of nanopore arrays in freestanding SiN and graphene membranes". Nanotechnology 29 (14): 145302. doi:10.1088/1361-6528/aaabce.
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  15. ^ Bandara, Y. M. N. D. Y.; Karawdeniya, B. I.; Dwyer, J. R. (2019). "Push-button method to create nanopores using a Tesla-coil lighter". ACS Omega 4 (1): 226-230. doi:10.1021/acsomega.8b02660.
  16. ^ Kemmishtree (March 29, 2026). "making pores with a $20 Tesla coil lighter". EQBio-OS.
  17. ^ "Company records". Molecular Reality Corporation. October 2026.
  18. ^ Fleischer, R. L.; Price, P. B.; Walker, R. M. (1965). "Tracks of charged particles in solids". Science 149 (3682): 383-393. doi:10.1126/science.149.3682.383.
  19. ^ Apel, P. (2001). "Track etching technique in membrane technology". Radiation Measurements 34 (1-6): 559-566. doi:10.1016/S1350-4487(01)00228-1.
  20. ^ Siwy, Z.; Fuliński, A. (2002). "Fabrication of a synthetic nanopore ion pump". Physical Review Letters 89 (19): 198103. doi:10.1103/PhysRevLett.89.198103.
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