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Solid-state nanopores: fabrication and applications
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Electrical Engineering, Solid-State Electronics. Uppsala University.
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Nanopores are of great interest in study of DNA sequencing, protein profiling and power generation. Among them, solid-state nanopores show obvious advantages over their biological counterparts in terms of high chemical stability and reusability as well as compatibility with the existing CMOS fabrication techniques. Nanopore sensing is most frequently based on measuring ionic current through a nanopore while applying a voltage across it. When an analyte passes through the pore, the ionic current temporarily changes, providing information of the analyte such as its size, shape and surface charge. Although many magnificent reports on using solid-state nanopores have appeared in the literature, several challenges still remain for their wider applications, which include improvement of fabrication reproducibility for mass production of ultra-small nanopores and minimization of measurement instability as well as control of translocation speed and reduction of background noise. This thesis work explores different techniques to achieve robust and high throughput fabrication of sub-10 nm nanopores for different applications.

The thesis starts with presenting various fabrication techniques explored during my PhD studies. Focused ion beam method was firstly employed to drill nanopores in free-standing SiNx membranes. Sub-10 nm nanopores could be obtained with a focused helium ion beam. But the fabrication throughput was limited with this technique. A new fabrication process combing electron beam lithography (EBL) with reactive ion etching/ion beam etching, which is compatible with the existing CMOS fabrication technology, was developed to realize a high throughput, mass production of nanopores in free-standing SiNx membranes. However, the smallest size that could be controllably achieved with this process was around 40 nm, which is still far from sub-10 nm in size required for, e.g., DNA sequencing. Finally, by using anisotropic etching of single-crystal silicon in KOH solution, sub-5 nm truncated pyramidal nanopores were mass produced with good process controllability in a silicon-on-insulator (SOI) substrate. In addition, nanopore arrays were also successfully fabricated using a modified EBL based fabrication process.

Then, several sensing application examples using either single nanopores or nanopore arrays were investigated. Translocation of nanoparticles, DNA and proteins were demonstrated using the fabricated single nanopores or nanopore arrays in a single freestanding membrane. Moreover, the kinetics and mechanism of the lipid bilayer formation in nanopore array, aiming to prevent non-specific adsorption, were studied using ionic current measurements. In addition, individual addressability of a solid-state nanopore array on separated freestanding membranes was realized by integrating microfluidics and a customized multiplexer.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. , p. 82
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1890
Keywords [en]
solid-state nanopore, truncated-pyramidal nanopore, nanopore array, pore size reduction, individual addressability, microfluidics, translocation.
National Category
Engineering and Technology
Research subject
Engineering Science with specialization in Electronics
Identifiers
URN: urn:nbn:se:uu:diva-399726ISBN: 978-91-513-0838-8 (print)OAI: oai:DiVA.org:uu-399726DiVA, id: diva2:1379290
Public defence
2020-02-21, Polhemsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2020-01-31 Created: 2019-12-16 Last updated: 2020-03-05
List of papers
1. Generalized Noise Study of Solid-State Nanopores at Low Frequencies
Open this publication in new window or tab >>Generalized Noise Study of Solid-State Nanopores at Low Frequencies
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2017 (English)In: ACS Sensors, ISSN 2379-3694, Vol. 2, no 2, p. 300-307Article in journal (Refereed) Published
Abstract [en]

Nanopore technology has been extensively investigated for analysis of biomolecules, and a success story in this field concerns DNA sequencing using a nanopore chip featuring an array of hundreds of biological nanopores (BioNs). Solid-state nanopores (SSNs) have been explored to attain longer lifetime and higher integration density than what BioNs can offer, but SSNs are generally considered to generate higher noise whose origin remains to be confirmed. Here, we systematically study lowfrequency (including thermal and flicker) noise characteristics of SSNs measuring 7 to 200 nm in diameter drilled through a 20-nmthick SiNx membrane by focused ion milling. Both bulk and surface ionic currents in the nanopore are found to contribute to the flicker noise, with their respective contributions determined by salt concentration and pH in electrolytes as well as bias conditions. Increasing salt concentration at constant pH and voltage bias leads to increase in the bulk ionic current and noise therefrom. Changing pH at constant salt concentration and current bias results in variation of surface charge density, and hence alteration of surface ionic current and noise. In addition, the noise from Ag/AgCl electrodes can become predominant when the pore size is large and/or the salt concentration is high. Analysis of our comprehensive experimental results leads to the establishment of a generalized nanopore noise model. The model not only gives an excellent account of the experimental observations, but can also be used for evaluation of various noise components in much smaller nanopores currently not experimentally available.

Keywords
flicker noise, nanopore, electrical double layer, model, power spectrum density, low frequency range, Hooge’s theory
National Category
Other Electrical Engineering, Electronic Engineering, Information Engineering
Identifiers
urn:nbn:se:uu:diva-315230 (URN)10.1021/acssensors.6b00826 (DOI)000395047000017 ()
Funder
Swedish Research Council, 621-2014-6300Stiftelsen Olle Engkvist Byggmästare, 2016/39Swedish Foundation for Strategic Research
Note

Chenyu Wen and Shuangshuang Zeng contributed equally to this work.

Available from: 2017-02-10 Created: 2017-02-10 Last updated: 2019-12-16Bibliographically approved
2. Group behavior of nanoparticles translocating multiple nanopores
Open this publication in new window or tab >>Group behavior of nanoparticles translocating multiple nanopores
2018 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, no 22, p. 13483-13490Article in journal (Refereed) Published
Abstract [en]

Nanopores have been implemented as nanosensors for DNA sequencing, biomolecule inspection, chemical analysis, nanoparticle detection, etc. For high-throughput and parallelized measurement using nanopore arrays, individual addressability has been a crucial technological solution in order to enable scrutiny of signals generated at each and every nanopore. Here, an alternative pathway of employing arrayed nanopores to perform sensor functions is investigated by examining the group behavior of nanoparticles translocating multiple nanopores. As no individual addressability is required, fabrication of nanopore devices along with microfluidic cells and readout circuits can be greatly simplified. Experimentally, arrays of less than 10 pores are shown to be capable of analyzing translocating nanoparticles with a good signal-to-noise margin. According to theoretical predictions, more pores (than 10) per array can perform high-fidelity analysis if the noise level of the measurement system can be better controlled. More pores per array would also allow for faster measurement at lower concentration because of larger capture cross sections for target nanoparticles. By experimentally varying the number of pores, the concentration of nanoparticles, or the applied bias voltage across the nanopores, we have identified the basic characteristics of this multievent process. By characterizing average pore current and associated standard deviation during translocation and by performing physical modeling and extensive numerical simulations, we have shown the possibility of determining the size and concentration of two kinds of translocating nanoparticles over 4 orders of magnitude in concentration. Hence, we have demonstrated the potential and versatility of the multiple-nanopore approach for high-throughput nanoparticle detection.

Place, publisher, year, edition, pages
Washington: American Chemical Society (ACS), 2018
National Category
Nano Technology
Identifiers
urn:nbn:se:uu:diva-369418 (URN)10.1021/acs.analchem.8b03408 (DOI)000451246100048 ()30372031 (PubMedID)
Funder
Swedish Research Council, 621-2014-6300Stiftelsen Olle Engkvist Byggmästare, 2016/39
Available from: 2018-12-13 Created: 2018-12-13 Last updated: 2019-12-16Bibliographically approved
3. Rectification of protein translocation in truncated-pyramidal nanopores
Open this publication in new window or tab >>Rectification of protein translocation in truncated-pyramidal nanopores
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2019 (English)In: Nature Nanotechnology, ISSN 1748-3387, E-ISSN 1748-3395, Vol. 14, p. 1056-1062Article in journal (Refereed) Published
Abstract [en]

Solid-state nanopore technology presents an emerging single-molecule-based analytical tool for the separation and analysis of nanoparticles. Different approaches have been pursued to attain the anticipated detection performance. Here, we report the rectification behaviour of protein translocation through silicon-based truncated pyramidal nanopores. When the size of translocating proteins is comparable to the smallest physical constriction of the nanopore, the frequency of translocation events observed is lower for proteins that travel from the larger to the small opening of the nanopore than for those that travel in the reverse direction. When the proteins are appreciably smaller than the nanopore, an opposite rectification in the frequency of translocation events is evident. The maximum rectification factor achieved is around ten. Numerical simulations reveal the formation of an electro-osmotic vortex in such asymmetric nanopores. The vortex–protein interaction is found to play a decisive role in rectifying the translocation in terms of polarity and amplitude. The reported phenomenon can be potentially exploitable for the discrimination of various nanoparticles.

National Category
Nano Technology Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-384656 (URN)10.1038/s41565-019-0549-0 (DOI)000495608700014 ()31591525 (PubMedID)
Funder
Swedish Research Council, 621-2014-6300Swedish Research Council, 2016/39
Available from: 2019-06-07 Created: 2019-06-07 Last updated: 2019-12-16Bibliographically approved
4. Controlled size reduction and its underlying mechanism to form solid-state nanopores via electron beam induced carbon deposition
Open this publication in new window or tab >>Controlled size reduction and its underlying mechanism to form solid-state nanopores via electron beam induced carbon deposition
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2019 (English)In: Nanotechnology, ISSN 0957-4484, E-ISSN 1361-6528, Vol. 30, no 45, article id 455303Article in journal (Refereed) Published
Abstract [en]

Solid-state nanopores have drawn considerable attention for their potential applications in DNA sequencing and nanoparticle analysis. However, fabrication of nanopores, especially those of diameter below 30 nm, requires sophisticated techniques. Here, a versatile method to controllably reduce the diameter of prefabricated large-size pores down to sub-30 nm without greatly increasing the effective pore depth from the original membrane thickness is shown. This method exploits carbon deposition achieved via hydrocarbon evaporation, induced by an incident beam of electrons, and subsequent dissociation of hydrocarbon to solid carbon deposits. The carbon deposition employs a conventional scanning electron microscope equipped with direct visual feedback, along with a stable hydrocarbon source nearby the sample. This work systematically studies how electron beam accelerating voltage, imaging magnification, initial pore size and membrane composition affect the process of pore size reduction. Secondary electrons generated in the membrane material are confirmed to be the main cause of the dissociation of hydrocarbon. Thicker carbon deposited on one side than on the other of the membrane results in an asymmetric nanopore shape and a rectifying ionic transport. A physico-phenomenological model combined with Monte Carlo simulations is proposed to account for the observed carbon deposition behaviors.

Place, publisher, year, edition, pages
IOP PUBLISHING LTD, 2019
Keywords
solid-state nanopore, pore size reduction, electron beam induced carbon deposition, secondary electrons, effective pore depth, rectifying behavior
National Category
Nano Technology
Identifiers
urn:nbn:se:uu:diva-394045 (URN)10.1088/1361-6528/ab39a2 (DOI)000483100000001 ()31394513 (PubMedID)
Funder
Swedish Research Council, 621-2014-6300Swedish Foundation for Strategic Research , FFL15-0174
Available from: 2019-10-04 Created: 2019-10-04 Last updated: 2020-01-08Bibliographically approved
5. Mechanism and kinetics of lipid bilayer formation in solid-state nanopores
Open this publication in new window or tab >>Mechanism and kinetics of lipid bilayer formation in solid-state nanopores
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2020 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 36, no 6, p. 1446-1453Article in journal (Refereed) Published
Abstract [en]

Solid-state nanopores provide a highly versatile platform for rapid electrical detection and analysis of single molecules. Lipid bilayer coating of the nanopores can reduce nonspecific analyte adsorption to the nanopore sidewalls and increase the sensing selectivity by providing possibilities for tethering specific ligands in a cell-membrane mimicking environment. However, the mechanism and kinetics of lipid bilayer formation from vesicles remain unclear in the presence of nanopores. In this work, we used a silicon-based, truncated pyramidal nanopore array as the support for lipid bilayer formation. Lipid bilayer formation in the nanopores was monitored in real time by the change in ionic current through the nanopores. Statistical analysis revealed that a lipid bilayer is formed from the instantaneous rupture of individual vesicle upon adsorption in the nanopores, differing from the generally agreed mechanism that lipid bilayer forms at a high vesicle surface coverage on a planar support. The dependence of the lipid bilayer formation process on the applied bias, vesicle size, and concentration was systematically studied. In addition, the nonfouling properties of the lipid bilayer coated nanopores were demonstrated during long single-stranded DNA translocation through the nanopore array. The findings indicate that the lipid bilayer formation process can be modulated by introducing nanocavities intentionally on the planar surface to create active sites or changing the vesicle size and concentration.

National Category
Physical Chemistry Biophysics
Identifiers
urn:nbn:se:uu:diva-399725 (URN)10.1021/acs.langmuir.9b03637 (DOI)000514759200008 ()31971393 (PubMedID)
Funder
Swedish Research Council, 621-2014-6300Swedish Research Council, 2017-04475Swedish Cancer Society, CAN 2017/430Knut and Alice Wallenberg Foundation, KAW 2015.0127Knut and Alice Wallenberg Foundation, KAW 2016.0231
Available from: 2019-12-16 Created: 2019-12-16 Last updated: 2020-03-30Bibliographically approved
6. A nanopore array of individual addressability enabled by integrating microfluidics and a multiplexer
Open this publication in new window or tab >>A nanopore array of individual addressability enabled by integrating microfluidics and a multiplexer
2019 (English)In: IEEE Sensors Journal, ISSN 1530-437X, E-ISSN 1558-1748, Vol. 20, no 3, p. 1558-1563Article in journal (Refereed) Published
Abstract [en]

Solid-state nanopores (SSN) are of significant potential as a versatile tool for chemical sensing, biomolecule inspection, nanoparticle detection, etc. High throughput characterization of SSN in an arrayed format is highly desired for a wide range of applications. Herein, we demonstrate a novel design to integrate an SSN array with microfluidics and a multiplexer. Ionic current measurement on each nanopore can then be individually addressed fluidically and/or electrically with minimum cross talk (electric leakage). This integration provides a scalable platform for automated high-throughput, low-cost, and rapid electrical characterization potentially of a large number of SSN.

Keywords
individual addressability, integration, microfluidics, multiplexer, solid-state nanopores
National Category
Other Electrical Engineering, Electronic Engineering, Information Engineering
Identifiers
urn:nbn:se:uu:diva-397405 (URN)10.1109/JSEN.2019.2947713 (DOI)
Funder
Swedish Research Council, 621-2014-6300
Available from: 2019-11-20 Created: 2019-11-20 Last updated: 2020-01-29Bibliographically approved

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