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Solid-State Nanopores for Sensing: From Theory to Applications
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.ORCID iD: 0000-0003-4395-7905
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Nanopore based sensing technology has been widely studied for a broad range of applications including DNA sequencing, protein profiling, metabolite molecules, and ions detection. The nanopore technology offers an unprecedented technological solution to meeting the demands of precision medicine on rapid, in-field, and low-cost biomolecule analysis. In general, nanopores are categorized in two families: solid-state nanopore (SSNP) and biological nanopore. The former is formed in a solid-state membrane made of SiNx, SiO2, silicon, graphene, MoS2, etc., while the latter represents natural protein ion-channels in cell membranes. Compared to biological pores, SSNPs are mechanically robust and their fabrication is compatible with traditional semiconductor processes, which may pave the way to their large-scale fabrication and high-density integration with standard control electronics. However, challenges remain for SSNPs, including poor stability, low repeatability, and relatively high background noise level. This thesis explores SSNPs from basic physical mechanisms to versatile applications, by entailing a balance between theory and experiment.

The thesis starts with theoretical models of nanopores. First, resistance of the open pore state is studied based on the distribution of electric field. An important concept, effective transport length, is introduced to quantify the extent of the high field region. Based on this conductance model, the nanopores size of various geometrical shapes can be extracted from a simple resistance measurement. Second, the physical causality of ionic current rectification of geometrically asymmetrical nanopores is unveiled. Third, the origin of low-frequency noise is identified. The contribution of each noise component at different conditions is compared. Forth, a simple nano-disk model is used to describe the blockage of ionic current caused by DNA translocation. The signal and noise properties are analyzed at system level.

Then, nanopore sensing experiments are implemented on cylinder SiNx nanopores and truncated-pyramid silicon nanopores (TPP). Prior to a systematic study, a low noise electrical characterization platform for nanopore devices is established. Signal acquisition guidelines and data processing flow are standardized. The effects of electroosmotic vortex in TPP on protein translocation dynamics are excavated. The autogenic translocation of DNA and proteins driven by the pW-level power generated by an electrolyte concentration gradient is demonstrated. Furthermore, by extending to a multiple pore system, the group translocation behavior of nanoparticles is studied. Various application scenarios, different analyte categories and divergent device structures accompanying with flexible configurations clearly point to the tremendous potential of SSNPs as a versatile sensor.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. , p. 108
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1825
Keywords [en]
solid-state nanopore, ionic current, current blockage, effective transport length, noise, surface charge, translocation, biomolecule, electroosmotic flow, vortex, autogenic translocation, multiple nanopores
National Category
Nano Technology Electrical Engineering, Electronic Engineering, Information Engineering
Research subject
Engineering Science with specialization in Electronics
Identifiers
URN: urn:nbn:se:uu:diva-384667ISBN: 978-91-513-0689-6 (print)OAI: oai:DiVA.org:uu-384667DiVA, id: diva2:1327122
Public defence
2019-09-06, Polhemsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2019-08-12 Created: 2019-06-19 Last updated: 2019-08-23
List of papers
1. Physical Model for Rapid and Accurate Determination of Nanopore Size via Conductance Measurement
Open this publication in new window or tab >>Physical Model for Rapid and Accurate Determination of Nanopore Size via Conductance Measurement
2017 (English)In: ACS SENSORS, ISSN 2379-3694, Vol. 2, no 10, p. 1523-1530Article in journal (Refereed) Published
Abstract [en]

Nanopores have been explored for various biochemical and nanoparticle analyses, primarily via characterizing the ionic current through the pores. At present, however, size determination for solid-state nanopores is experimentally tedious and theoretically unaccountable. Here, we establish a physical model by introducing an effective transport length, L (eff) that measures, for a symmetric nanopore, twice the distance from the center of the nanopore where the electric field is the highest to the point along the nanopore axis where the electric field falls to e-(1)of this maximum. By G = sigma(s0)/L-eff, a simple expression S-0=/(G, sigma, h, beta) is derived to algebraically correlate minimum nanopore cross-section area S (0)to nanopore conductance G, electrolyte conductivity a, and membrane thickness h with (3 to denote pore shape that is determined by the pore fabrication technique. The model agrees excellently with experimental results for nanopores in graphene, single-layer MoS2, and ultrathin SiNx films. The generality of the model is verified by applying it to micrometer-size pores.

Keywords
nanopores, physical model, effective transport length, algebraic solution, conductance measurement in electrolyte
National Category
Nano Technology
Identifiers
urn:nbn:se:uu:diva-340952 (URN)10.1021/acssensors.7b00576 (DOI)000414238600021 ()28974095 (PubMedID)
Funder
Swedish Research Council, 621-2014-6300
Available from: 2018-02-13 Created: 2018-02-13 Last updated: 2019-06-19Bibliographically approved
2. Zero-Depth Interfacial Nanopore Capillaries
Open this publication in new window or tab >>Zero-Depth Interfacial Nanopore Capillaries
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2018 (English)In: Advanced Materials, ISSN 0935-9648, E-ISSN 1521-4095, Vol. 30, no 9, article id 1703602Article in journal (Refereed) Published
Abstract [en]

High-fidelity analysis of translocating biomolecules through nanopores demands shortening the nanocapillary length to a minimal value. Existing nanopores and capillaries, however, inherit a finite length from the parent membranes. Here, nanocapillaries of zero depth are formed by dissolving two superimposed and crossing metallic nanorods, molded in polymeric slabs. In an electrolyte, the interface shared by the crossing fluidic channels is mathematically of zero thickness and defines the narrowest constriction in the stream of ions through the nanopore device. This novel architecture provides the possibility to design nanopore fluidic channels, particularly with a robust 3D architecture maintaining the ultimate zero thickness geometry independently of the thickness of the fluidic channels. With orders of magnitude reduced biomolecule translocation speed, and lowered electronic and ionic noise compared to nanopores in 2D materials, the findings establish interfacial nanopores as a scalable platform for realizing nanofluidic systems, capable of single-molecule detection.

Place, publisher, year, edition, pages
WILEY-V C H VERLAG GMBH, 2018
Keywords
2D nanopores, biomolecules, 1, f noise, mechanical stability, translocation speed
National Category
Condensed Matter Physics Atom and Molecular Physics and Optics Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-350489 (URN)10.1002/adma.201703602 (DOI)000426491600035 ()
Funder
Swedish Research Council, 621-2014-6300]EU, European Research Council, 335879
Available from: 2018-05-09 Created: 2018-05-09 Last updated: 2019-06-19Bibliographically approved
3. On rectification of ionic current in nanopores
Open this publication in new window or tab >>On rectification of ionic current in nanopores
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2019 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882Article in journal (Refereed) Submitted
National Category
Nano Technology
Identifiers
urn:nbn:se:uu:diva-384653 (URN)
Available from: 2019-06-07 Created: 2019-06-07 Last updated: 2019-06-19
4. 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: 2019-06-19Bibliographically approved
5. On nanopore DNA sequencing by signal and noise analysis of ionic current
Open this publication in new window or tab >>On nanopore DNA sequencing by signal and noise analysis of ionic current
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2016 (English)In: Nanotechnology, ISSN 0957-4484, E-ISSN 1361-6528, Vol. 27, article id 215502Article in journal (Refereed) Published
Abstract [en]

DNA sequencing, i.e., the process of determining the succession of nucleotides on a DNA strand, has become a standard aid in biomedical research and is expected to revolutionize medicine. With the capability of handling single DNA molecules, nanopore technology holds high promises to become speedier in sequencing at lower cost than what are achievable with the commercially available optics-or semiconductor-based massively parallelized technologies. Despite tremendous progress made with biological and solid-state nanopores, high error rates and large uncertainties persist with the sequencing results. Here, we employ a nano-disk model to quantitatively analyze the sequencing process by examining the variations of ionic current when a DNA strand translocates a nanopore. Our focus is placed on signal-boosting and noise-suppressing strategies in order to attain the single-nucleotide resolution. Apart from decreasing pore diameter and thickness, it is crucial to also reduce the translocation speed and facilitate a stepwise translocation. Our best-case scenario analysis points to severe challenges with employing plain nanopore technology, i.e., without recourse to any signal amplification strategy, in achieving sequencing with the desired single-nucleotide resolution. A conceptual approach based on strand synthesis in the nanopore of the translocating DNA from single-stranded to double-stranded is shown to yield a 10-fold signal amplification. Although it involves no advanced physics and is very simple in mathematics, this simple model captures the essence of nanopore sequencing and is useful in guiding the design and operation of nanopore sequencing.

Keywords
nanopore; DNA sequencing; ionic current; model; series resistance; noise; signal
National Category
Other Electrical Engineering, Electronic Engineering, Information Engineering
Identifiers
urn:nbn:se:uu:diva-295968 (URN)10.1088/0957-4484/27/21/215502 (DOI)000374507600013 ()27095148 (PubMedID)
Funder
Swedish Research Council, 621-2014-6300
Available from: 2016-06-11 Created: 2016-06-11 Last updated: 2019-06-19Bibliographically approved
6. 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 1748-3395Article in journal (Refereed) Published
National Category
Nano Technology
Identifiers
urn:nbn:se:uu:diva-384656 (URN)10.1038/s41565-019-0549-0 (DOI)
Available from: 2019-06-07 Created: 2019-06-07 Last updated: 2019-10-10
7. Autogenic analyte translocation in nanopores
Open this publication in new window or tab >>Autogenic analyte translocation in nanopores
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2019 (English)In: Nano Energy, ISSN 2211-2855, E-ISSN 2211-3282, Vol. 60, p. 503-509Article in journal (Refereed) Published
Abstract [en]

Nanopores have been widely studied for power generation and single-molecule detection. Although the power level generated by a single nanopore based on electrolyte concentration gradient is too low to be practically useful, such a power level is found sufficient to drive analyte translocation in nanopores. Here, we explore the simultaneous action of a solid-state nanopore as a nanopower generator and a nanoscale biosensor by exploiting the extremely small power generated to drive the analyte translocation in the same nanopore device. This autogenic analyte translocation is demonstrated using protein and DNA for their distinct shape, size and charge. The simple device structure allows for easy implementation of either electrical or optical readout. The obtained nanopore translocation is characterized by typical behaviors expected for an ordinary nanopore sensor powered by an external source. Extensive numerical simulation confirms the power generation and power level generated. It also reveals the fundamentals of autogenic translocation. As it requires no external power source, the sensing can be conducted with simple readout electronics and may allow for integration of high-density nanopores. Our approach demonstrated in this work may pave the way to practical high-throughput single-molecule nanopore sensing powered by the distributed energy harvested by the nanopores themselves.

Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Nano Technology
Identifiers
urn:nbn:se:uu:diva-384648 (URN)10.1016/j.nanoen.2019.03.092 (DOI)000467774100056 ()
Funder
Swedish Research Council, 621-2014-6300Stiftelsen Olle Engkvist Byggmästare, 2016/39
Available from: 2019-06-07 Created: 2019-06-07 Last updated: 2019-06-19Bibliographically approved
8. 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: 2019-06-19Bibliographically approved

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