Microtomy-fabricated two-dimensional nano-slits enable single molecule biosensing

Abstract

Nanofluidic devices have emerged as a powerful sensor for single-molecule studies. Among these, biological nanopores have demonstrated remarkable capabilities, ranging from detecting epigenetic modifications in DNA to showing promising results for developing protein sequencing technologies. Despite extensive research, their solid-state counterparts, such as solid-state nanopores and nano-slits, have not achieved comparable success. Unlike biological nanopores, where bacterial proteins can spontaneously insert into lipid membranes to create thousands of atomically identical copies, their solid-state counterparts lack a similarly straightforward and scalable fabrication method. This inability to consistently produce multiple devices with the same precision in dimensions as biological systems remains a significant barrier to their academic and industrial adoption and applications in molecular sensing. Towards this direction, we show the potential of ultramicrotomy-based fabrication of atomically smooth two-dimensional (2D) nanocapillaries and their applications in biosensing. This precise and straightforward method enabled the sustainable production of several hundred molybdenum disulfide-based 2D nano-slits with identical cross-sectional dimensions and tunable lengths from layered crystals. Here, we demonstrated DNA sensing with these 2D nano-slits using the resistive ionic current blockade technique. This robust microtomy technique accelerates production from a single device over 2–3 weeks to hundreds of identical nano-slit biosensors in parallel within the same period. In addition to 1/f noise analysis, these MoS₂ nano-slits reveal diverse topological local conformations of DNA during translocation.

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Ashok Keerthi

Dr Ashok Keerthi is a Presidential Academic Fellow in the Department of Chemistry at the University of Manchester. He obtained his PhD from the National University of Singapore in 2014, followed by postdoctoral research at the Max Planck Institute for Polymer Research (Germany) and the University of Manchester. In 2019, he was awarded the prestigious Ramsay Memorial Fellowship, followed by the Presidential Fellowship in 2022, enabling him to establish his independent research group. His current research focuses on the bottom-up synthesis of chiral nanographenes, graphene nanoribbons, and angstrom-scale channels. His group investigates the chemistry and physics of molecular architectures and 2D capillaries.

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Introduction

Developing tools for ultrasensitive single-molecule studies is crucial, particularly in biology. The nano-fluidic devices, such as nanopores and nano-slits, have emerged as a promising toolbox for studying on a single molecule level.¹ These devices have shown potential applications such as DNA sensing^2–5 and sequencing⁶ to proof of concepts in developing protein sequencing techniques.^7–9 For instance, biological nanopores have already been successfully commercialized for DNA sequencing and established as a major part of the next generation sequencing tools. In contrast, even though solid-state nanopores offer chemical, mechanical and thermal stability over biological nanopores, they are yet to prove their practical viability for DNA sequencing. A few among the major challenges include the difficulty in reproducing solid-state nanopores with atomic precision in dimensions and a lack of control over the translocation speed of biopolymers through the pore. On the other hand, synthetic nano-slits are also gaining momentum for their applications in bio-sensing and studies on structural configurations as well as translocation dynamics of biopolymers.^2,3 Given these increasing academic and industrial interests¹⁰ and to aid further exploratory research, various fabrication techniques have been developed since the late 20th century.

Traditionally, solid-state nanopores are drilled solely on free-standing membranes of silicon, silicon nitride or other 2D materials using a mix of techniques such as transmission electron microscopy (TEM), focused ion beam (FIB), or dielectric breakdown.^11–14 Nano-slits, on the other hand, are produced through either top-down or bottom-up approaches.¹⁵ These include molecular self-assembly, lithography, and chemical routes.¹⁶ In the context of bio-sensing applications on an industrial level, particularly for DNA sensing, the ability to create nano-slits and nanopores with both precise control over their inner dimensions and scalability is important. Developing efficient and scalable fabrication methods that deliver nanopores/nano-slits with atomically smooth inner walls or constrictions is essential for further advancements in this field and industry adoption.¹⁷

In this study, we demonstrate the biosensing capabilities of 2D nano-slits, fabricated through a sustainable and scalable method.¹⁸ This approach utilizes ultramicrotomy to slice 2D capillaries, which are constructed from molybdenum disulfide (MoS₂) 2D crystals. This precise method allowed us to detect DNA translocation through MoS₂-based 2D nano-slits using the resistive ionic current blockade technique. MoS₂ is particularly interesting compared to other 2D materials due to several reasons, such as better optoelectronic properties.¹⁹ It also has better chemical tunability compared to graphene,²⁰ owing to its reactive sulfur atoms enabling different surface chemistries, making it useful for selective sensing of biomolecules.^21,22 The low adhesion of DNA molecules to MoS₂ significantly mitigates channel clogging, enhancing the reliability of translocation measurements.^23,24 Several studies also depicted MoS₂ as a potential candidate for proteomics and genomics.^9,25–27Hence, MoS₂ exhibits higher sensitivity in biomolecular sensing applications.^23,28,29 Apart from these reasons, MoS₂ is practically viable for use with the ultramicrotomy slicing technique, where graphite and hBN fail due to their weak interlayer forces and lubricity between layers as well as their poor cohesion with epoxy resin.¹⁸

In contrast to other techniques, ultramicrotomy-based production of 2D nano-slits works under atmospheric conditions and has the potential for scalable fabrication. For instance, conventional fabrication methods typically require 2–4 weeks to produce a single two-dimensional nano-slit device¹⁵ based on the expertise. In contrast, once we prepare one of the layered crystal stacks on the epoxy resin block, we can fabricate hundreds of nanocapillary devices with minimal variability using the ultramicrotomy fabrication technique, significantly reducing both time and cost. For example, we were able to produce up to 200 nano-slits within 20 minutes.

While our prior study¹⁸ introduced the ultramicrotomy technique for fabricating 2D channels, in this work, we implement this scalable fabrication approach for the first time for label-free detection of DNA. Prior work primarily focused on the fabrication of ultrathin membranes, whereas this study explores their direct application in biosensing, filling an important gap. This transition from fabrication to functional application is a crucial step forward, establishing ultramicrotomy-assisted nano-slits as a powerful and scalable platform for nanofluidic biosensing. We have explored possible substrates with micropores such as silicon and silicon nitride (SiN_x) to fabricate 2D nano-slit devices for ion and bio-molecule transport (see the detailed description in the fabrication section) and re-cycling of substrates for sustainable fabrication, making this technique accessible for the wider scientific community. This method also offers utmost flexibility in defining the channel length and provides scope for the fabrication of multi-slit systems, which has attracted significant interest in DNA sensing recently.^30,31 By demonstrating DNA sensing using MoS₂-based 2D nano-slit devices fabricated via the ultramicrotomy technique, we aim to significantly advance the emerging biosensing applications that utilize synthetic nanochannels.¹⁰

Device fabrication

We employ ultramicrotomy to fabricate multiple 2D nano-slit devices with channel lengths of 300 nm from a single 2D nanocapillary, van der Waals (vdW) assembly containing a tri-crystal stack, using our reported procedure.¹⁸ Our methodology commences with a vdW heterostructure incorporating top and bottom MoS₂ crystals with thickness ranging from 100 to 200 nm, wherein the middle MoS₂ crystal (thickness, 8.4 nm) has been lithographically patterned and etched to form parallel channels, defining its width (W = 100 nm) and height (H = 8.4 nm) with 250 nm spacing between them (Fig. 1E).¹⁵ The middle/spacer crystal is sandwiched between the top and bottom MoS₂ crystals, with a few tens of microns in lateral dimensions, to result in 2D capillaries within the vdW assembly. This 2D capillary stack of MoS₂ crystals was fabricated in a cleanroom environment and then embedded in the epoxy resin under ambient conditions. The epoxy resin block containing 2D nanocapillaries was subsequently sectioned using ultramicrotomy (Fig. 1A), yielding numerous membrane slices (300 nm thickness, which is the channel length L for 2D nano-slits). The sliced resins were collected using a poly(propylene) carbonate film coated on a polydimethylsiloxane (PPC/PDMS) substrate (Fig. 1B) and then transferred to a 5 × 25 μm² microhole made on a 500 nm thick SiN_x membrane, which was fabricated using standard photolithography and dry etching techniques (Fig. 1C; also refer to ESI's† Methods section). Fig. 1F shows the optical microscopy image of the final device.

Fig. 1 Schematic illustration of 2D nano-slit device fabrication and the measurement setup. (A) Ultramicrotomy slicing of the MoS₂ vdW structure embedded inside a resin block using a diamond knife. An enlarged schematic of a sliced resin with dimensions of a 2D nano-slit. (B) The sliced resin is picked up using a PPC/PDMS substrate. (C) The sliced resin is transferred onto a SiN_x membrane with a pre-drilled hole. (D) Schematic of the voltage-biased custom-built PEEK flow cell used for ion and DNA translocation/sensing experiments with Ag/AgCl electrodes. (E) AFM image and the line scan profile of the etched channels on the MoS₂ spacer crystal. (F) Optical microscopy images of the MoS₂-based 2D nano-slit device.

DNA sensing with microtomy-fabricated MoS₂-based 2D nano-slits

The microtomy-fabricated 2D nano-slit device is sandwiched between custom-built polyether ether ketone (PEEK) flow cells, which are filled with 3 mL of 4 M LiCl aqueous electrolyte in both reservoirs (Fig. 1D). The LiCl electrolyte is used for improving the signal to noise ratio of the ionic current signal.³² The standard Ag/AgCl electrodes are used for applying the voltage bias and to measure ionic current simultaneously, using an Axopatch 200B amplifier, which is controlled by a customized LABVIEW software program. To showcase the device's potential for DNA sensing applications, a 5000 base-pair DNA (no limit DNA fragments, product number: SM1731, Thermo Fisher Scientific) is used in a 4 M LiCl electrolyte with 40 mM Tris-HCl (AccuGene) and 4 mM EDTA (Flurochem) buffer solutions. For the experiment, 5 μL of stock solution (0.5 μg μL⁻¹) of DNA is injected into a negatively biased reservoir of the PEEK flow cell. The sampling is done at 100 kHz and later digitally filtered using a Gaussian low pass filter at 3 kHz. The data analysis is carried out with the standard Transalyzer MATLAB software package.³³

Right after fabrication, the MoS₂ nano-slits are made conductive via repetitive voltage cycling³⁴ with a 4 M LiCl solution (section 4 in the ESI†). The stable current vs. voltage (I–V) curve is shown in Fig. 2A. The device we report here has three conducting 2D nano-slits, each having the following dimensions: length (L) = 300 nm, width (W) = 100 nm, and height (H) = 8.4 nm; these dimensions are comparable to those of nano-slits (made via different fabrication routes) reported in the literature.^2,3 The theoretical conductance, G, is calculated using eqn (1), which turns out to be 1.46 × 10⁻⁷ S, where the experimental conductance for this device is 1.55 × 10⁻⁷ S. This shows that the device is stable and working as expected in the electrolyte solution (section 3 in the ESI†).

where n is the number of channels (n = 3 in this case), σ is the conductivity of the electrolyte,³⁵ which is 17.6 S m⁻¹ for 4 M LiCl, W is the width, H is the height and L is the length of the 2D nano-slits.

Fig. 2 (A) Current vs. voltage (I–V) curve of 2D nano-slits fabricated from MoS₂ nanocapillary in 4 M LiCl aqueous electrolyte. (B) Steady ionic current through 2D nano-slits at different operating voltages; the average current is shown in the y-axis and represented by dashed lines. (C) Power spectral density of the device at different operating voltages.

The example of steady ionic current measured at different operating voltages is shown in Fig. 2B. The power spectral density (PSD) diagrams of the corresponding voltages are plotted and shown in Fig. 2C. As expected, the PSD diagram shows the typical pink/flicker noise and white noises³⁶ before getting cut off by the 100 kHz sampling frequency limit. As flicker noise (<100 Hz) is known to depend on device properties,^36,37 1/f noise was further explored with our unique device architecture. In 2D channels, the flicker noise is known to deviate from empirical Hooge's law (eqn (2)). It follows the frequency relation (eqn (3)) in a low frequency regime (f < 100 Hz), and the exponent (x) is known to depend on the channel properties.³⁷

Here, I is the ionic current, N is the number of ions inside the pore, and α is the numeric constant.

where x = 1 + a and ‘a’ ranges from 0 to 0.5. According to Robin et al.,³⁷ for pristine graphite and pristine boron nitride, the exponent is reported as 1.3 and 1.2, respectively, whereas in our microtomy-fabricated MoS₂ 2D nano-slits, the exponent value was found to be 1.5 by averaging over different voltage cases, as shown in Fig. S1.† The corresponding MATLAB codes used for data analysis can also be found in the ESI.†

The DNA (5 kbp linear dsDNA) translocation at a low voltage was dominated by spike events with this MoS₂-based 2D nano-slit device, consistent with the literature² (Fig. S6†). Spike events indicate the unsuccessful translocation of DNA, where the DNA tries to enter the nano-slit and withdraws due to an entropic barrier (Fig. 3C, section 5 in the ESI†). Furthermore, to overcome the entropic barrier, we have used a higher voltage of 400 mV for DNA translocation studies. Fig. 3A shows that we are able to detect the translocation of DNA through this nano-slit device in a non-destructive and label-free method. The representative figures of current blockades when a full DNA translocates through the slits are shown in Fig. 3B. This approach of using modulations in ionic current, inspired by the Coulter counter technique, is well known in the nanopore literature for characterization of the translocation of biomolecules.^38,39 For a first-order approximation, we have calculated the expected⁴⁰ current blockade when DNA translocates through the single nano-slit using eqn (4):

Fig. 3 (A) Current blockade vs. dwell time graph of DNA translocation through a 2D nano-slit device at 400 mV bias. (B) Representative current blockades of DNA translocating through a nano-slit. (C) Dwell time graph of DNA translocation and spike events. (D) Dwell time graph of DNA translocation events. (E) Gaussian-fitted current blockade graph of DNA translocation events.

Here, σ is the conductivity of the electrolyte (17.6 S m⁻¹ for 4 M LiCl solution), V_bias is the applied voltage bias (400 mV in this case), L is the length of the channel, which is 300 nm, and A is the effective cross-sectional area of the translocating molecule, where we approximated DNA as a cylinder with a maximum effective diameter of 2.3 nm.^41,42 The theoretical ionic current blockade calculated from eqn (4) is ∼0.1 nA per single channel. We have found that the average ionic current blockade in our device with three 2D nano-slits is around 0.25 nA (Fig. 3E) for an applied voltage bias of 400 mV. These confirm DNA translocation through the 2D nano-slit with various configurations such as loops, knots, folds, and so forth, as the nano-slit's height is more than three times DNA's diameter.

Under our measurement conditions (0.8 ng μL⁻¹ of dsDNA in the reservoir in 4 M LiCl with an applied bias of 400 mV), the translocation event rate is lower than that of the solid-state nanopore.²⁶ However, this low event rate (less than one event per second) is similar to that reported in our previous study with graphene nano-slits.² Therefore, it is extremely unlikely to have simultaneous multi-DNA translocations through our device with MoS₂-based 2D nano-slits. These 2D nano-slits with MoS₂ walls show a median dwell time of ∼27 ms (Fig. 3D), whereas a graphene nano-slit shows a median dwell time of ∼8 ms, under different experimental conditions.² This could also be due to different entry/exit configurations of microtomy-fabricated MoS₂ 2D nano-slits or DNA interactions with MoS₂ channel walls. Also, we have not observed any clogging of the nano-slit or permanent sticking of DNA inside the nano-slit device after the translocation measurements (Fig. S2†).

DNA topology investigations using MoS₂-based 2D nano-slits

The microtomy-fabricated 2D nano-slits with MoS₂ channel walls have a 2D constriction of ∼8.4 nm, lower than the persistence length of DNA. As demonstrated in previous studies, translocation through these nano-slits compels DNA to shift from a 3D configuration to a 2D or 1D shape, inducing knots and folds or unwinding to a linear polymer. Understanding DNA and protein folding in such constrained environments has significant implications for biology, affecting processes from DNA replication and protein catalysis to the cellular mechanisms underlying folding. Gel electrophoresis is currently the major bulk technique used to study DNA knots, and solid state nanopores were successfully used earlier to detect DNA knots.^43,44 Our studies using microtomy-fabricated MoS₂ 2D nano-slits reveal direct observations of diverse DNA folding patterns, highlighting the potential of these devices for advanced biosensing applications.

In our earlier work,² we have demonstrated that the mechanically exfoliated graphene does not interact with double-stranded DNA owing to its atomically smooth and inert surface of basal planes with a negligible number of defects/surface charge. With the help of molecular dynamics simulation and related theoretical discussion, we have verified that the folding and knots remain undisturbed while translocating through the slit due to this negligible interaction.² Similarly, in this case, 2D nano-slits of MoS₂ did not show a significant interaction with DNA compared to the unconfined graphene.⁴⁵ As expected, the DNA has maintained the loop and folding while translocating through the slit (Fig. 4, Fig. S8 in the ESI†). As is known from previous works on ionic current-based sensing,^2,43,44 the shape of the ionic current blockade can be correlated to the 3D topology of DNA translocating through the pore/slit. Here, in MoS₂ nano-slits, the event rate is less than one event per second, and the chances of multiple DNA translocating together/tailgating are extremely low. Hence, building upon the simulation and theoretical studies in our previous work on DNA in nanoconfinement,² we assign the current blockade to the topology of DNA translocating through these 2D nano-slits. As shown in Fig. 4, we detected different possible conformations of DNA folding for the first time with MoS₂-based 2D nano-slits (section 6 in the ESI†). As the height of the slit is less than the persistence length of DNA (H/L_p < 1, where H is the height of the slit (8.4 nm) and L_p is the persistent length of DNA (∼50 nm)), we are in the backfolded Odijk regime, and hence the type of folding, as shown in Fig. 4, is theoretically expected.⁴⁶ The probability distribution of different DNA foldings is provided in Fig. S9.† Moving forward, we aim to expand this investigation by exploring various device configurations and DNA lengths to further elucidate topological properties. We also hope to extend the application of this technique for studying G-quadruplexes, R-loops and other disease-relevant DNA folding and structural variations.

Fig. 4 Nano-slit microscopy for understanding the topology of DNA folding. (A) Schematic of DNA translocating through a 2D nano-slit. (B–H) Representative current blockades of DNA translocation in various configurations; unfolded DNA (I), semi-folded DNA on the left end (II), semi-folded DNA on the right end (III), two-times bent configuration in DNA (IV), partially folded DNA (V) and fully folded configuration (VI) and bent or partially folded DNA conformation (VII).

Conclusions

We demonstrated the biosensing capabilities of 2D nano-slits with MoS₂ channel walls fabricated using a scalable ultramicrotomy technique and showed their applications in DNA sensing. We also report the deviation of 1/f noise from empirical Hooge's law with an exponent value of 1.5. To explore the biosensing capabilities of our devices, we conducted electrophysiological testing using microtomy-fabricated MoS₂ 2D nano-slits. These measurements enabled real-time monitoring of ionic current fluctuations during DNA translocation, allowing us to directly observe distinct folding configurations. The high sensitivity and spatial resolution of these nano-slits underscore their potential for advanced single-molecule analysis and next-generation biosensing applications. This work, through sustainable and scalable fabrication of nano-slit devices with precise dimensions, paves the way to advance nano-slit technologies for applications in proteomics to an integral part of point-of-care devices. Currently, we are exploring the potential of these robust microtomy-fabricated, chemically tunable MoS₂ devices for selective biomolecule sensing and size-based filtering of biomolecules.

Data availability

The data supporting this article have been included as part of the ESI.† The GitHub links for all the codes used are also added in the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

A. K. acknowledges the Royal Society grant ICA\R1\231014, and the Presidential Fellowship from the University of Manchester. B. R. acknowledges funding from the European Union's H2020 Framework Programme/European Research Council Starting Grant (852674 – AngstroCAP), the Royal Society University Research Fellowship (URF\R1\180127, URF\R\231008), Philip Leverhulme Prize PLP-2021-262, and EPSRC New Horizons grant EP/X019225/1. B. R. and A. K. acknowledge EPSRC strategic equipment grant EP/W006502/1. M. S. P. acknowledges the Commonwealth Split-Site PhD Scholarship and the UoM-IISc joint degree studentship award. This work was partly supported by the Scientific and Useful Profound Research Advancement (SUPRA) Program of the Science Engineering Research Board (SERB) under grant SPR/2021/000275. AK acknowleges the UK-India Education Research Innovation (UKIERI) award supported by the British Council (IND/CONT/G/23-24/37).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d5nr01832c

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