and fluid transport
in nanofluidic devices has received considerable attention over the
past two decades due to unique transport properties exhibited at the
Phenomena such as double layer overlap,
high surface-to-volume ratios, surface charge, ion-current rectification,
and entropic barriers can influence transport in and around nanofluidic
structures because the length scales of these forces and the critical
dimensions of the device are similar. Advances in micro- and nanofabrication
techniques provide the ability to design a variety of well-defined
nanofluidic geometries to study these phenomena and their effects
on ion and fluid transport. Integration of micro- and nanofluidic
structures into lab-on-a-chip devices permits increased functionality
that is useful for a range of analytical applications.
This Review focuses on recent advances in nanofabrication techniques
as well as studies of fundamental transport in nanofluidic devices.
Nanopores, nanochannels, and nanopipets are three common nanofluidic
structures that have been influential in studying nanofluidic transport.
Because of space limitations, we have limited the scope of this Review
to studies with these three structures, and we focus our attention
primarily on work published between January 2011 and August 2014.
We do not discuss work with carbon nanotubes,
Figure 1 shows examples
of the three nanofluidic
geometries discussed here. Nanopores are typically formed perpendicular
to the plane of a substrate and are characterized by a critical limiting
dimension, which is measured by scanning electron microscopy (SEM),
transmission electron microscopy (TEM), or conductance measurements.
Pores are fabricated in a variety of materials, e.g., poly(carbonate),
poly(ethylene terephthalate), or silicon nitride, and can have an
asymmetric (Figure 1a) or symmetric (Figure 1b) shape, depending on the fabrication
Symmetric pores are either cylindrically shaped with a constant critical
dimension determined by electron microscopy or hourglass-shaped with
a critical dimension at the center of the pore. Although electron
microscopy is capable of measuring exterior pore dimensions, the exact
inner geometry is often unknown and may contain an asymmetry between
two symmetric features, e.g., cigar-shaped pores. Asymmetric nanopores
typically have a narrow tip and a wide base with a funnel-shaped geometry
along the pore axis. Tip and base dimensions are measured by SEM,
but the exact pore geometry is often unknown. Nanochannels often refer
to in-plane structures with either symmetric (Figure 1c) or asymmetric (Figure 1d)
Channels may be confined to the nanoscale in depth, width, or both,
depending on the fabrication method. Nanochannels are commonly fabricated
in glass and polymer substrates and characterized by SEM and atomic
force microscopy (AFM). The in-plane nature of these channels allows
the integration of well-defined features into more complex geometries,
and any two-dimensional (2D) channel architecture can be designed.
Nanopipets are specialized nanopores fabricated from pulled glass
or fused-silica capillaries (Figure 1e,f).
The geometry of a nanopipet is conically shaped with a critical tip
diameter of tens to hundreds of nanometers, which can be measured
by electron microscopy. Unlike nanopores and nanochannels, nanopipets
can be easily coupled with position control, which allows the tip
of the nanopipets to be positioned in specific locations or used in
scanned probe microscopies.
Nanopores, nanochannels, and nanopipets are
three common nanofluidic
platforms. Nanopores are typically out-of-plane structures and have
either an asymmetric or symmetric geometry. Conical nanopores have
a wide base as shown in panel a that tapers to a critical nanometer-sized
tip. Reprinted from ref (24). Copyright 2012 American Chemical Society. Symmetric
similar to the SiN pore in panel b, have a circular geometry with
a nanometer-scale diameter. Reprinted with permission from ref (186). Copyright 2011
Chemical Society. Nanochannels are commonly fabricated as in-plane
structures. (c) A rectangular nanochannel is milled in a glass substrate
between two microchannels by a focused ion beam instrument. (d) Asymmetric
nanochannels fabricated by electron-beam lithography, polymer replication,
and electron-beam induced etching have a wide base and a narrower,
critical tip dimension. Reprinted with permission from ref (34). Copyright 2012 John
& Sons, Inc. Nanopipets have asymmetric geometries that taper
toward a critical tip diameter. Quartz capillaries are pulled to fabricate
nanopipets with inner diameters below 75 nm, which are used for (e)
electrospray ionization of peptides and (f) discrimination of charged
surfaces. Panel e is reprinted from ref (248). Copyright 2013 American Chemical Society.
Panel f is reprinted from ref (127). Copyright 2011 American Chemical Society.
Advances in Nanofabrication
availability and sophistication of nanofabrication techniques
have contributed significantly to the recent growth of nanofluidics.
Although colloid and membrane sciences have explored
nanofluidic phenomena with nano- and microparticles and in porous
media for many decades, fabrication methods to form individual, well-defined
nanoscale structures are a major development over the past two decades.
A variety of methods including high-energy beam milling, damage-track
etching, dry and wet etching, laser writing, laser pulling, and imprint
lithography have become established nanofabrication techniques and
remain widely used in nanofluidic research as discussed in previous
in nanofabrication seek to improve device-to-device reproducibility,
decrease critical dimensions, and ease device production. In this
section, we summarize recent advances in existing nanofabrication
techniques in addition to new nanofabrication methods developed in
the time frame of this Review for the three nanofluidic geometries
Fabrication methods such
as high-energy beam
milling or selective etching of ion tracks through a polymer membrane
are commonly used to fabricate nanopores perpendicular to the substrate
surface. Sculpting fabricated pores by low energy ion- or electron-beam
irradiation allows both the shape and size of these pores to be tuned
to a desired geometry.
Transmission electron microscopes can
fabricate sub-10 nm nanopores by irradiating a thin membrane with
a focused, high-energy beam of electrons.
Ablation of the membrane results in the formation of an individual
nanopore. Milling through a metal film deposited onto a silicon nitride
membrane is used to create nanogap electrodes adjacent to a pore for
Drilled pores are tuned
with electron-beam sculpting which uses a low energy electron beam
(e-beam) to controllably close a larger opening to single-nanometer
A focused ion beam (FIB) instrument
is also able to mill single nanopores in thin membranes by two primary
methods. Typical ion-beam drilling with gallium ions produces individual
nanopores with diameters of tens of nanometers,
and narrowing of these pores is possible by atomic layer
FIB milling can also produce
pores as small as 6 nm in diameter in cooled substrates (<173 K)
due to reduced surface diffusion.
ion beam milling drills nanopores directly in unprocessed silicon
nitride membranes and generates pores with diameters <4 nm with
low electronic noise.
in silicon nitride membranes by a helium ion beam also have reduced
background fluorescence compared to pores milled with gallium ions.
Similar to e-beam sculpting, ion-beam sculpting
employs a low energy ion beam to precisely close an opening to diameters
as small as 1–2 nm.
by an e-beam form a hydrocarbon layer, effectively lengthening the
pore, whereas pores sculpted by an ion beam incorporate gallium ions
and become hourglass shaped with a wider average pore diameter compared
to pores drilled directly.
are also formed by selective ion-track etching in thin membranes and
are widely used for current-rectification studies. A drawback to the
use of track-etched pores is the unknown inner pore geometry. Conductance
measurements and SEM observations more accurately reconstruct and
predict the longitudinal geometry of pores in track-etched membranes,
which has a direct impact on rectification.
The geometries of pores in track-etched membranes can be tuned to
a degree, where asymmetric etching of polymer membranes creates funnel-shaped
pores and single-sided surfactant-assisted etching produces bullet-like
Alternative methods to fabricate nanopores aim to decrease
time and production cost. Single nanopores are fabricated by nanofractures
in commercially available capillaries as an inexpensive nanofabrication
Metal nanoparticle-assisted plasma
etching produces conically shaped nanopores in silicon substrates.
Conventional photolithography and wet chemical
etching generate arrays of pyramidal nanopores with an average side
length of 60 nm, which are employed as a reusable lithography mask.
Nanoapertures are also produced by a low cost,
corner lithography technique in which isotropic thinning generates
a nitride nanodot which is removed to form a nanoscale opening.
Nanoporous materials such as anodized aluminum
can be modified by atomic layer
deposition to effectively reduce pore diameters
and increase performance.
Nanochannels are ideal geometries for
investigating fundamental transport and biological sensing
due to the ability to control and characterize
all three channel dimensions. Additionally, nanochannels in the plane
of the substrate allow optical measurements to be combined with electrical
measurements to provide complementary information. One-dimensional
(1D) and two-dimensional (2D) nanochannels are fabricated in-plane
by a variety of methods. Conventional microfabrication techniques
such as photolithography and wet chemical etching are used to fabricate
1D nanoscale-depth microchannels,
techniques such as e-beam lithography and focused ion beam milling
are typically needed to fabricate 2D structures that are confined
to the nanoscale in both lateral dimensions.
Electron beam lithography
(EBL) uses an electron beam to replicate a desired pattern on a surface
coated with a thin, electron-sensitive resist. Fabrication of 2D nanochannels
is achieved by either selective removal of the exposed positive-tone
resist or unexposed negative-tone resist. Removal of exposed positive-tone
resist uncovers only the desired sections of the substrate, and the
nanochannel design can be directly transferred to the substrate, for
example, by reactive ion etching (RIE).
Conversely, removal of unexposed negative-tone resist leaves raised
nanofluidic features on the substrate. The pattern on the substrate
is then used as a master to mold nanofluidic channels in polymer materials.
Nanofluidic masters can also be shaped by e-beam
induced etching to produce smaller critical dimensions.
EBL can also deposit metal films onto a substrate
by e-beam deposition
to form nanogap
electrodes in nanochannel arrays.
Similarly, FIB milling can fabricate 2D nanochannels in any arbitrary
pattern. A beam of focused ions, commonly Ga ions, is rastered along
a specified pattern, directly milling the feature into the substrate.
Channel depth is precisely controlled by varying either the beam current
or the dose of ions that impinge the surface. Charging of insulating
materials due to the accumulation of ions on the substrate surface
is circumvented by deposition of a conductive sacrificial layer, e.g.,
a metal film, onto the substrate or bathing the surface with electrons
Milling through a sacrificial
minimizes redeposition of material during
milling and reduces swelling. Channels less than 5 nm wide are milled
with an FIB instrument in quartz through a relatively thick metal
film, e.g., 100 nm, which takes advantage of the narrowed width of
structures milled deeper into a substrate.
FIB milling can also create masters from which polymer nanochannel
devices are cast.
Similar to nanopore fabrication, alternative
methods for nanochannel
fabrication are being explored to increase throughput and decrease
production costs. EBL and FIB milling provide precise features but
are both expensive and time-consuming processes. Nanochannels with
high lateral fidelity are fabricated by nanoimprint lithography (NIL).
Unlike EBL and FIB milling, NIL is a high-throughput technique used
to fabricate 1D and 2D nanochannels by mechanically pressing a fabricated
master into a curable resist.
is somewhat expensive and time-consuming to produce but is able to
replicate a number of devices. Imprint resist spun onto a substrate
is brought into physical contact with a master, and the resist is
cured leaving the imprinted nanochannel structures in the resist layer.
A hybrid fabrication process that combines hot embossing and inverse
UV-lithography forms micro- and nanochannels in SU-8 from a master
with high reproducibility.
exfoliated graphene oxide sheets has successfully created massive
arrays of nanochannels.
printing of an alkane monolayer onto a mica surface is a cost-effective
technique to produce 1D nanochannels.
Nanopipets are fabricated from glass or
quartz capillaries by application of heat to soften the capillary
followed by physically pulling the capillary to separate the capillary
into two sister pipets. Mechanical pullers provide precise control
over the fabrication process with heat provided by a metal filament
or laser source. Control over pulling parameters allows the pipet
geometry to be tuned to a degree with different parameters providing
different taper lengths and opening diameters. After being pulled,
the pipet tip geometry can be further tuned with microforges or through
polishing to alter the tip geometry.
advanced methods such as ion or electron beam radiation
and FIB milling
pipet tips with high precision.
Additional functionality is
imparted on nanopipets by deposition of electrode material or functionalization
of the glass surface with specific chemical recognition elements.
Several strategies have been explored to deposit carbon and metal
films to obtain nanoelectrodes that combine high-resolution imaging
with chemical analysis through scanning ion conductance microscopy
(SICM) or scanning electrochemical microscopy (SECM). Flowing gases
such as methane, acetylene, or butane inside the pipet and subsequent
pyrolysis of the gas deposits carbonaceous material on the inner wall
of a nanopipet.
Changing the ratio of methane
to carrier gas and pyrolysis time influences the amount of carbon
deposited inside the nanopipet tip.
1:1 ratio of methane to argon gas produces nanoelectrodes with carbon
layers on the inner wall of the quartz pipet that blocked the pipet
channel and contained a cavity at the tip of the pipet. Cavity depth
depends on tip diameter and pipet geometry. However, a relatively
short chemical vapor deposition (CVD) time of 30 min and a lower methane
to argon ratio yield pipets with an open path in the middle. The cavity
at the tip is able to sample nanoliter volumes of sample through capillary
action. Carbon ring electrodes are fabricated by CVD of parylene C
onto a nanopipet, followed by pyrolysis of the parylene C layer at
900 °C under an inert nitrogen atmosphere to form a conformal
layer of amorphous carbon. The carbon ring electrode is exposed by
FIB milling of the nanopipet tip after deposition of an insulating
layer of parylene C.
are formed by thermally evaporating or sputtering a conductive metal
layer onto a pipet, depositing an insulating layer around the metal,
and exposing the end of the capillary by FIB milling.
Metal electrodes can also be formed at the tip of carbon
coated nanopipets by electrochemical deposition of platinum at the
A metal disk shaped electrode
can be fabricated at the tip of a nanopipet by electroless deposition
of gold nanoparticles at a liquid–liquid interface supported
by the nanopipet. The metal precursor is present in an aqueous phase,
the reductant is present in an organic phase, and potential developed
at the interface leads to spontaneous formation of metal nanoparticles
which block the tip of the pipet, forming a disk-shaped nanoelectrode.
at the nanoscale is uniquely affected by physical phenomena
such as surface charge, double layer overlap, and ion current rectification,
which are typically absent or insignificant in microfluidic devices.
Fundamental studies of these forces are essential to design nanofluidic
devices effective for analytical applications. Here, we provide a
brief overview of electrostatic and electrokinetic effects and focus
on how they impact transport through nanofluidic structures.
Fixed charges on a surface
attract oppositely charged ions in solution, creating an electrical
double layer (EDL) to maintain electrical neutrality. The potential
distribution within the counterion-rich double layer is described
by the Poisson–Boltzmann equation and decays away from the
surface. Surface charge density and electrolyte concentration affect
the thickness of the EDL, which is typically on the order of 1–30
Double layers are thin at high salt
concentrations and low surface charge density but increase in thickness
with lower salt concentrations and higher surface charge density.
In nanofluidic structures, double layers on opposite surfaces can
interact and even overlap, which can create permselective openings
that repel co-ions. The structure of the double layer dictates nanofluidic
transport; consequently, the impact of solution composition and surface
modification on EDL structure is of great interest.
sandwiched between a pair of sensing electrodes is used to study the
effects of decreasing ion concentration on EDL structure.
As predicted by theory, decreased ion concentration
causes expansion of the EDL, which can merge with the EDL associated
with the opposing electrode. Proton distributions near a glass wall
are captured by super-resolution laser-induced fluorescence to gain
insight into the EDL structure.
impedance spectroscopy probes capacitance and geometric effects which
are resolved by varying the electrolyte concentration.
Previous studies have
shown that nanochannels
exhibit higher conductivity than bulk ionic solutions at low electrolyte
concentrations due to a large portion of current carried in the double
layer by counterions.
As channel dimensions
decrease, the contribution of surface charge becomes greater, and
a lower threshold conductance is observed.
Surface-charge governed ion transport occurs in nanochannels
fabricated with layered materials.
effect influences transport not only in a nanofluidic structure but
also affects transport away from the structure. Electric current is
perturbed at a distance from a nanopore dictated by the Dukhin length
in order to meet charge conservation at a pore entrance.
Chemical modification can reduce overall surface
charge which, in turn, reduces channel conductivity.
Simulations predict that long channels modified with polyelectrolyte
chains exhibit higher conductance due to the increased number of counterions
necessary to balance the charge, but channels modified with neutral
polymers have a lower overall conductance.
Application of an electric field
along a fluidic conduit with surface charge induces movement of mobile
ions in the electrical double layer, and viscous forces in solution
drag adjacent fluid layers along in the same direction, creating electroosmotic
flow (EOF). The profile of EOF in microchannels is plug-like, and
velocity increases as ionic strength decreases. However, EOF in a
nanochannel is influenced when the double layer extends into the channel
at low salt concentrations, giving rise to parabolic flow profiles
that mirror the potential distribution and result in a reduced average
EOF at low ionic strength is reduced in rectangular
nanochannels with half-depths <100 nm when compared to EOF in microchannels.
Electroosmotic mobilities in the nanochannels
exhibit maxima at κh ∼ 4, where κ
is the Debye–Hückel parameter and h is the channel half-depth, indicating that the
degree of double
layer overlap depends on both channel dimensions and Debye length.
Physical factors that affect electroosmotic flow have been investigated
theoretically. Changes in surface properties that affect EOF are induced
by field-effect control, and models predict that the EOF velocity
can be tuned by a nanofluidic field-effect transistor.
Surface modifications modulate EOF, and simulations
of channels with polyelectrolyte coatings predict different flow profiles
compared to bare nanochannels.
EOF at the junction of a microchannel and nanochannel results in a
pressure gradient which improves separation efficiency in nanofluidic
This pressure gradient can
be used for electroosmotically induced pumping and increased flow
rates at low voltages.
Electrophoresis is the movement of
charged particles in an electric field and separates particles based
on charge and hydrodynamic volume. The electrophoretic mobility of
particles can be reduced in nanochannels due to interactions with
the channel surface and electrical double layer.
Electrophoresis of rigid spheres is studied numerically,
and previous models are extended to include effects of multi-ion species.
These studies also suggest that particle mobility
depends on the magnitude and direction of EOF. Another model of electrophoretic
motion examines the effects of surface potential and double-layer
thickness on transport. This model concludes that higher viscosity
droplets travel more slowly, and droplets with lower surface potential
actually induce faster particle movement due to ions being drawn into
the double layer, which decreases polarization effects.
flow through channels
or nanopores creates an electric streaming current due to the movement
of ions in the bulk and EDL. Accumulation of ions downstream generates
an electric streaming potential that depends on surface charge, electrolyte
concentration, and channel dimensions.
With these factors, streaming potential measurements can be used
to calculate the zeta potential of channels.
Double layer overlap
leads to a decrease in the streaming potential and must be accounted
for by correction factors.
show an increase in the magnitude of streaming potential in ion-selective
nanopores, which is attributed to the finite size of ionic species
and must be accounted for in numerical predictions.
Sidewalls lead to a decrease in streaming potential in low aspect-ratio
channels due to the reduction in pressure-driven velocity.
Analytical solutions to quantify streaming potential
and electroviscous effects that account for EDL thickness predict
three regimes of EDL influence on the streaming potential that depend
on conduction current.
In cases of strong
double layer overlap (κa ∼ 1, where a is the capillary
radius), the effective viscosity is governed by the EOF velocity,
and competing flows in opposite directions reduce overall net flow.
(ICR) is a result of uneven transference of cations and anions across
a nanostructure, and ion current is greater in one direction than
in the other (Figure 2a).
ICR is observed in nanofluidic devices that contain either
an asymmetric geometry, asymmetric surface charge, physical blockage
near the nanostructure, or a combination of these features. ICR was
first observed in quartz nanopipet electrodes
and later studied extensively with conically shaped nanopores in
The degree to which
a device rectifies current is quantified by the rectification ratio,
which is the absolute value of the ratio of ion current measured at
two applied potentials of equal magnitude but opposite polarity. ICR
is analogous to solid-state electronic diodes, and fabrication of
nanofluidic devices with diode-like behavior is of particular interest.
rectification is preferential current transport in
nanofluidic structures that have an asymmetry in geometry (panel a),
surface charge, or blockage of an opening. (b) Conical nanopores modified
with a spiropyran molecule rectify ion current when illuminated with
UV light, and ion current rectification changes direction when pH
is changed. Reprinted with permission from ref (100). Copyright 2012 John
Wiley & Sons, Inc. (c) Simulations and (d) experiments show that
the magnitude of ion current rectification in nanopores with single-nanometer
diameters depends on cation size. Reprinted from ref (113). Copyright 2014 American
Chemical Society. (e) Ion-current rectification at the interface between
a nanopipet and a charged surface occurs in opposite directions for
oppositely charged surfaces. Reprinted from ref (128). Copyright 2013 American
The extent and direction
of rectification depends on surface charge
and polarity of the applied potential and can be controlled
by changes in electrolyte concentration,
and field-effect modulation.
ICR is influenced by surface modifications that affect
the surface charge of the device and alter the response of a channel
to external stimuli. For example, pH changes can stimulate the transition
between swollen and collapsed states of pH-responsive molecules which
vary the degree of rectification.
change can also be sensed by ICR through incorporation of amine-terminated
polymer brushes inside conical nanopores that shrink or swell with
As previously demonstrated
in glass nanopores,
PET nanopores are
gated optically by irradiating photolabile protecting groups with
with different molecules at opposite
ends are able to tune transport. Conical nanopores modified with DNA
oligomers exhibit both reversible voltage and pH gating and have extraordinarily
high rectification at high pH.
pH-dependent rectification is enhanced by hydrophobic C10 and C18
thiol gates on one side of a nanopore due to the increased resistance
of the hydrophobic layer.
pH- and light-responsive
nanochannels are realized by modification with dual-responsive malachite
(Figure 2b). Cigar-shaped nanochannels modified
at opposite ends by different molecules act as double-gated ion pumps.
A smart homopolymer that is both pH and temperature sensitive produces
reversible switching of rectification in glass nanopores.
C4-DNA motors attached to PET pores change
conformation by accepting or releasing protons generated indirectly
by UV irradiation of a photoinduced OH– emitter,
malachite green carbinol base (MGCB), and adsorb cetyltrimethylammonium
bromide (CTAB) molecules that physically block the pore.
UV exposure causes an increase in pH which,
in turn, causes the DNA motors to stretch to a single-stranded structure
that can adsorb more blockers and effectively reduce current compared
to DNA motors at low pH that form a shorter, i-motif structure with
fewer adsorbed blockers. Asymmetric surface charge distribution is
established in highly ordered nanochannel arrays in porous anodic
alumina membranes by functionalizing the surface with amine groups
to induce pH-dependent ICR.
of nanopore surfaces also permits nanoscale sensing.
Calcein-modified channels bind calcium ions, which reduce conductance
in the high-conductance state.
lactoferrin is also sensed by nanopores modified with iron-terpyridine.
PET pores modified with β-cyclodextrin
discriminate between enantiomers of histidine.
Interestingly, l-histidine selectively binds to
the β-cyclodextrin, leading to an increase in the rectification
ratio, but d-histidine does not interact with the host molecule,
resulting in no change. Rectification also occurs in structures with
symmetric pore geometries and uniform charge distributions when a
nanoparticle partially blocks the pore entrance, and direction of
rectification depends on the charge of both the functionalized polystyrene
particle and pore.
of the electrolyte influence rectification ratios due to cooperation
and competition between geometry-induced asymmetric transport and
diffusive ion flow.
A switch from a
high-conductance state to a low-conductance state occurs over a very
short, tunable voltage window (10 mV) for nanopores separating a low
conductivity solution from a high conductivity solution due to negative
differential electrolyte resistance and bistable fluid flow.
As an externally applied pressure increases, the potential at which
a ∼80% decrease in current is observed becomes more negative.
Pressure-driven flow disrupts cation and anion distributions in and
adjacent to nanopores and can eliminate ICR in large nanopores (∼200
nm radii) but has a negligible effect on pores with radii below 30
In small nanopores (3–25
nm in diameter), the size of monovalent
cations impacts the degree of current rectification. Figure 2c shows that experimental
results are in good agreement
with simulations and that rectification increases with increasing
cation size for these small pores.
of current flow in weakly selective pores suggest that intrapore depletion
and enrichment zones are responsible for ICR and that inversion of
rectification is possible.
in highly selective pores, concentration depletion external to the
pore leads to rectification, and rectification inversion is possible
at high applied voltages. Another theoretical model suggests that
diode-like current behavior is possible in the presence of a concentration
gradient, and ion selectivity may be reversed if the gradient is high
Functionalization of nanostructures
in close proximity to nanopores alters their rectification behavior.
Modification of the outer membrane of neutral nanopores with polyelectrolyte
varies the current rectification and has also been modeled.
This modification is advantageous for multiple reasons, including
easier access of outer membranes to modification and enhanced rectification
due to the immobilized surface charge. Theoretical work suggests that
gating performance and modulation of conductance states by field effect
modulation of the zeta potential is higher when the background electrolyte
concentration and pH are both low.
Nanopipets exhibit ICR when the tip of the pipet is similar in
dimension to the Debye length
tip is blocked by a charged surface. Current rectification is reversible
in quartz nanopipets that are modified by immersing the pipet in a
low-conductance states that correlate to the collapse and swelling
of the polymer are switched in the presence of saccharide or changes
in pH. The direction of rectification in nanopipets is also reversed
by modification of the surface with poly(ethylene imine) (PEI), a
positively charged polymer,
and the magnitude
of rectification depends on electrolyte concentration.
PEI-modified pores decorated with glucose oxidase
reverse the direction of rectification again and reduce AlCl4
a chitosan-modified nanopipet detects changes in ICR that correlate
to binding of Cu2+ and obtain the associated binding affinity
of the ion.
For nanopipets, ICR
is affected by the tip diameter, surface charge
of the tip,
and cone angle of the pipet.
When nanopipets are in close proximity to a
charged surface, the ICR can also be influenced.
This effect distinguishes cationic and anionic substrates through
the observation of ICR changes in a pipet held tens to hundreds of
nanometers from the surface.
is further supported by finite element simulations (Figure 2e).
describe conditions in which current is enhanced as a pipet approaches
a surface due to electroosmotic flow separation.
A substrate with a surface charge density 10-fold higher
than a pipet dominates and dictates ICR instead of the pipet. The
interplay between the pipet and surface is seen in simultaneous topographic
measurements and substrate surface charge mapping by SICM.
In these studies, ac techniques enhance the
determination of surface charge and provide additional insight into
nanoscale interfacial chemistry.
Nanofluidic Diodes and
flow in nanofluidic devices is analogous to the behavior of electronic
with the exception that ions in solution rather than electrons
act as the charge carriers.
electrodes in nanochannels and concentration gradients near a nanofluidic
structure act as a controllable gate to effectively alter current
flow through the channel.
A cylindrical thermosensitive channel
is formed with triblock copolymer brushes whose configuration and
phase behavior depend on temperature.
Closed channels are opened by increased temperature until a threshold
temperature is reached, and further increases in temperature cause
the channels to reclose. Bipolar membranes also exhibit nonlinear
current behavior in a process similar to PN-junctions in electronic
transistors. Use of polyphosphonium as a polycation in bipolar membrane
diodes allows a large window of usable gate voltages.
Stacking of bipolar membranes in series suppresses
ion accumulation, produces faster off-switching with reduced hysteresis,
and forms a fluidic AND gate.
of diode-like pores conclude that ICR is solution-dependent, and a
maximum in ICR is observed due to the balance between increased ion
enrichment inside the pore and depletion outside the reservoir.
Addition of a concentration gradient
acts as a gate electrode near
the nanostructure and modulates voltage, which, in turn, influences
fluid transport and ICR. Electrostatic gating of nanochannels by tuned
gradients in ionic strength controls the release of fullerene derivatives.
Voltages applied to a gate electrode adjacent
to a nanochannel dictate the degree of rectification within the nanochannel.
Biasing potentials less than 1 V applied through
metal gate electrodes control the capture of DNA in 200 nm pores.
A potential applied to a gate electrode embedded
in a nanochannel is simulated and predicts that surface charge density
becomes more negative with increasing potential, resulting in increased
Additional simulations show that gated nanochannels
exhibit enrichment and depletion, depending on the polarity of the
surface charge and applied gate potential.
Simulations of changes in surface charge density of gated nanopores
suggest that modulation in pore conductance is dependent on pH, ionic
strength, and applied voltage.
Theoretical and experimental results with a three-electrode nanopore
show changes in the electric field induced by a working electrode
adjacent to a nanopore leads to ICR at high salt concentrations.
Active gating of semiconducting nanopores significantly
enhances rectification ratios.
FET-like arrays tune ICR through modulation of the potential applied
to a metal gate near the nanopore array.
Two conical nanopores aligned in parallel or series can also function
as a gating network.
on the orientation of both pores and direction of the applied potential.
Branched alumina nanochannels act like tunable nanofluidic diodes
due to the cooperative asymmetry of the branched structure.
Concentration Polarization and Sample Enrichment
ion flux and emergence of concentration gradients occur when potentials
are applied across microchannel-nanochannel junctions. When the electrophoretic
mobility of ions is greater than diffusive transport in the adjacent
microchannels, counterions are depleted on the feed side of the nanochannel
due to preferential transport through the charged channel and accumulate
on the other side. Simultaneously, co-ion transport through the same
channel is hindered, and concentration polarization (CP) results.
Charged molecules are enriched by the CP mechanism,
and preconcentration of limited samples is possible. If the electroosmotic
and electrophoretic forces are balanced, sample stacking can occur
at the boundary of the depletion region, away from the micro- and
elastomeric valves in PDMS devices act as nanoscale conduits and can
induce CP effects.
Such a device generates
103-fold preconcentration of fluorescein in a 2 mM lithium
carbonate solution in ∼270 s with a single channel. Nanoporous
membranes efficiently concentrate samples. Embedded nanoporous membranes
in nanofluidic paper devices enrich a fluorescent tracer by 40-fold,
and nanofractures formed by nanoparticle-assisted
electric breakdown between two microchannels concentrate a protein
sample 104-fold in 60 min.
Polyacrylamide gels integrated into microchannels form a micro-
and nanochannel junction that yields 600-fold enrichment within 120
Controlled hydrodynamic flow adjacent
to a Nafion nanojunction membrane limits the propagation of CP by
continuously replenishing charge carriers to the depletion region
and confining the CP region to a triangular region near the junction.
At high hydrodynamic inflows, the limiting-current
region is eliminated, which results in increased power efficiency.
Moreover, enzyme activity increases in regions of enriched targets.
Figure 3a shows the preconcentration of quenched,
dye-labeled nanoparticles concentrated near a Nafion membrane.
Trypsin molecules in solution cleave proteins
bound to the nanoparticles, and the cleaved proteins fluoresce. In
another example, a Nafion membrane is cast in a microfracture region
as a microfabrication-free technique to electrokinetically
stack and enrich DNA.
Sample enrichment at
junctions between micro- and nanochannels
occurs when there is preferential ion transport. (a) A nanoporous
membrane integrated in a microchannel produces an enrichment region
that increases with time. Reprinted from ref (151). Copyright 2014 American
Chemical Society. (b) Nanoconstrictions along a nanochannel concentrate
fluorescently tagged proteins by electrodeless dielectrophoresis.
Reprinted from ref (154). Copyright 2012 American Chemical Society. (c) Pressure-driven
concentrates fluorescent nanobeads in a bypass micro- and nanofluidic
device. Reprinted from ref (155) with permission of The Royal Society of Chemistry.
2013 The Royal Society of Chemistry.
Regions of cathodic and anodic focusing occur in the same
structures by hydrostatic-pressure stabilization of CP effects.
Dielectric nanoconstrictions embedded in nanofluidic
devices act as field-focusing lenses that generate molecular traps
and dams by dielectrophoresis for rapid protein enrichment (Figure 3b).
Figure 3c shows electroless preconcentration in silicon
nanofluidic devices with a symmetric pressure-driven crossflow to
concentrate particles at a discrete point. In the same device, an
asymmetric pressure-driven mode generates a streaming potential
and concentrates E. coli bacteria
50-fold in only 40 s. Proteins are enriched in nanochannels with a
pH gradient along the length of the channel by balancing the forces
of pH-dependent charge and viscous drag.
Alternatively, proteins are focused at different ends of a nanochannel
by concentration gradient focusing.
nonlinear voltage behavior associated with CP is affected by
A microfluidic device with a photopolymerized,
nanoporous polyacrylamide membrane has pH fluctuations >1.5 pH
which are mapped spatiotemporally and depend strongly on buffer properties.
Three-dimensional numerical simulations of
a nanofunnel positioned between two straight nanochannels indicate
that enrichment and depletion zones propagate away from the nanofunnel
in a high-conductance state but remain localized in a low-conductance
Simulations of CP development
and vortex generation also found that the electrophoretic mobilities
of counterions in a nanoporous membrane affect CP, i.e., CP strength
increases with counterion mobility. Moreover, preconcentration increases
with increasing electric potentials that generate vortex flow and
a slow-flow zone near the membrane.
Nanofluidic devices with critical
dimensions comparable to the size of a particle can be used for resistive-pulse
sensing (RPS), which is a label-free, nondestructive method to detect
individual particles. Transient reductions in ion current, or pulses,
occur when particles pass through an electrically biased conduit and
are proportional to particle size. Conduit dimensions are tuned to
detect specific particle sizes, and the ability to readily manufacture
nanoscale features has increased the types of nanoscale particles
that can be sensed. This technique is of particular interest as a
means of rapid genomic sequencing.
can be categorized as in-plane or out-of-plane depending on device
orientation and particle motion. Out-of-plane devices incorporate
nanopores perpendicular to the substrate surface whereas in-plane
devices have nanopores fabricated parallel to the substrate surface.
Pulse characteristics encode information about particle and pore
geometry as well as information about interactions between the analyte
and pore. Particle size relative to the pore dimensions dictates the
amplitude of a current pulse, and pores can be modified to better
match particle size and increase pulse amplitude. Figure 4a shows that decreasing
pore diameters produce larger
changes in conductance.
unknown sizes are measured with nanopores calibrated with particles
of known sizes.
Pores fabricated in
ultrathin silicon nitride membranes characterize the binding of a
drug or molecule to an RNA complex by measuring differences in pulse
amplitude for bound and unbound molecules.
Monitoring bare and bound antibodies produce similar changes in
in nanoscale conduits with dimensions comparable
to the size of the analyte of interest. (a) Nanopipets sense DNA molecules
with increasing sensitivity as pore diameter is reduced. Reprinted
from ref (166). Copyright
2013 American Chemical Society. (b) DNA translocates through amine-functionalized
nanopores, and translocation time through the pore depends on the
surface-charge density, which is tuned by pH. Reprinted with permission
from ref (191). Copyright
2013 American Chemical Society. (c) In-plane nanochannel with two
pores in series detects each hepatitis B virus particle twice during
transit through the nanochannel. Reprinted from ref (32). Copyright 2011 American
Chemical Society. (d) DNA driven through a long nanochannel in a glass
substrate is detected electrically as the DNA passes a shorter, lateral
nanochannel. Reprinted from ref (38). Copyright 2012 American Chemical Society.
Interactions between particles
and nanopores produce pulses with
variable widths and may be electrostatic or size-based in nature.
Pulse shapes depend on the shape of the constriction,
and the effect of pore geometry on pulse shape
as well as deformation of hydrogel particles
within the pore
are studied with PET
nanopores. The size, charge, and zeta potential of translocating particles
can also be extracted from pulse width.
The surface charge of nanoparticles is also measured by applying
pressure across a nanopore to oppose electrokinetic flow.
When the opposing pressure completely counteracts the electrokinetic
flow, the particle velocity is zero, and current pulses are not observed.
Pore sculpting alters the shape of drilled nanopores and has a direct
impact on pulse shape, i.e., pores drilled directly by an ion beam
have smaller average diameters than pores sculpted to the same critical
dimension by an ion beam.
diameters of the sculpted pores result in lower pulse amplitudes,
and longer translocation times occur in the case of the e-beam sculpted
pores. Biological pores are capable of detecting trace levels of cocaine
by binding drug molecules to DNA aptamers that become lodged in the
pore and cause an extended current blockage.
Longer DNA molecules have longer translocation times compared
shorter DNA molecules in a fixed-length nanochannel, and an asymmetric
bipolar pulse leads to rapid separation of different-length molecules.
Binding of proteins to DNA aptamers immobilized
on nanobeads show increased pulse widths.
Deformable channels with reduced cross sections generate DNA-translocation
events with reduced frequency and longer pulse widths.
The buffer pH can cause nanoparticles to expand,
and swollen particles are forced to squeeze through the pore, resulting
in increased pulse widths.
serum albumin (BSA) molecules in various conformations pass through
a TEM-drilled nanopore and are detected electrically,
the denatured forms of BSA produce wider pulse widths than
nondenatured BSA because of increased interactions with the pore walls.
Carboxylate-modified polystyrene spheres create asymmetric pulses
passing through size-tunable nanopores, and pulse-shape is particle-size
Understanding the processes
by which particles enter nanoscale
constrictions and how the particles behave while inside a constriction
is critical to designing devices with optimized performance. Access
resistance dominates particle translocation and barely fluctuates
during particle translocation.
devices, nanoscale confinement in single-particle data suggests a
narrow escape, whereas ensemble measurements suggest crowding effects,
which drive escape even at low particle concentration.
The motion of fluorescent DNA is visualized
and affected by both electroosmosis and electrophoresis, and capture
volumes for small nanopores are calculated by finite element simulations.
Coating of nanopores increases the functionality
of nanopore sensors. Nanopores coated with a fluid lipid bilayer mimic
biological pores, and the coating minimizes clogging and nonspecific
binding as well as reduces translocation times.
Chemical modification of PET membranes with triethylene glycol suppresses
electroosmotic flow and minimizes particle adsorption for characterization
of hepatitis B virus capsids.
Figure 4b shows the difference in pulse widths for pores
coated with 3-aminopropyltrimethoxy-silane (APTMS) and surface charge
tuned with pH.
As pH is increased from
6 to 8, surface charge density is reduced and translocation times
for DNA decrease.
RPS devices fabricated in-plane have the added
advantages of incorporation
of multiple sensors in series as well as optical monitoring to better
understand transport through a device. Figure 4c shows a nanochannel with two nanopores
in series for detection
of hepatitis B virus capsids, and the pore-to-pore transit time is
used to determine the electrophoretic mobility of the capsids.
A pulse is recorded each time a capsid passes
through a pore, and a pulse pair corresponds to a single capsid passing
through the two pores in series. With a different in-plane design,
electrodes with a nanoscale gap embedded in a nanopore detect and
count metal-encapsulated fullerenes and DNA oligomers.
Lateral conductance measurements of dsDNA molecules
in a long nanochannel are made through shorter channels positioned
perpendicular to the translocation channel (Figure 4d).
Measurements of electrophoretic
mobility and optical detection of molecules are possible in this design,
and measuring current in a shorter channel produces higher signal-to-noise
ratios by minimizing the potential dropped along the channel. Another
in-plane method uses geometric nodes distributed along a nanochannel
to produce pulse shapes with distinct current signatures.
This design senses the presence of particles
even when the signal-to-noise ratios are low, as demonstrated by the
detection of HIV in human plasma. Simultaneous optical and electrical
sensing of single particles combines particle tracking and unambiguous
detection of fluorescently labeled beads at the nanoconstrictions
in an in-plane nanochannel with adjacent electrodes.
Rapid and cost-effective sequencing of DNA may be
RPS through electrical discrimination of individual DNA bases. Molecular
dynamics simulations suggest that tunneling currents through all four
DNA bases are statistically different and that transverse sensing
of translocating DNA molecules can discriminate among the bases.
FIB-milled nanopores with integrated tunneling
electrodes are used to detect DNA molecules by both tunneling current
and ion current.
Nanopores milled in
graphene nanoribbons also detect DNA translocation with a relatively
slow translocation speed.
of molecularly thin graphene nanogaps predict that the four bases
are distinguished by their electrical tunneling currents.
Ion conductance through the pore and electrical
conductance through the graphene are measured simultaneously and are
altered when a particle passes through the pore. Devices consisting
of silicon nanowires adjacent to a nanopore act as FET sensors to
detect the translocation of DNA molecules.
FET conductance and ionic current are recorded simultaneously and
may be used for DNA sequencing in the future. Two nanopores stacked
in series can estimate the electrophoretic mobility of DNA molecules
by measuring the time-of-flight between pores.
Transport of DNA molecules passing through a nanoconstriction
depends on the shape of the constriction. Simulations with graphene
as the sensing substrate predict that nanopores drilled through a
graphene monolayer with zigzag edges have significantly enhanced current
signals when DNA translocates through the pore.
Resistive-pulse sensing with conical nanopores in
glass membranes has an advantage over cylindrical nanopores because
the direction of particle translocation can be extracted from the
asymmetric pulse shape produced by conical pores.
This phenomenon is attributed to a nonuniform electric
field within the pore. Current pulses observed during particle translocation
transition from a single-peak pulse to a biphasic pulse consisting
of an increased current peak before the current decreases at high
negative potentials (<−0.4 V).
The biphasic nature of the pulse is a result of increased conductivity
from the surface charge of the translocating particle and the displacement
of ionic solution within the pore.
Efforts to make RPS more
quantitative have been directed toward
evaluation of solution concentration by correlating the current blockage
event and diffusion current of the particle to the orifice.
The effect of salt concentration on the translocation of DNA through
quartz nanopipets demonstrate that at high salt concentrations translocation
events result in a decrease in current, but at low salt concentrations,
DNA translocation actually increases the ionic current.
Label-free in-flow detection of single DNA
is possible as molecules pass by the nanopipet tip. Also, there are
efforts to use the peak shape and exploit the surface charge on the
nanopores to sense charged analytes bound to a nanoparticle surface.
Resistive-pulse sensing distinguishes between peptide-modified particles
and antibodies attached to these peptide-modified particles.
Current pulses produced by antibody-conjugated
particles and bare Au or Au-peptide nanoparticles occur at potentials
with opposite polarity and are oriented in opposite directions, which
enables selective detection of antibodies.
in nanochannel devices are of considerable interest for rapidly sorting
and sensing particles. Several nanofluidic mechanisms are used to
separate molecules with improved resolution and separation speed as
well as separation of nanometer-sized particles. Particles are often
separated by size, length, or charge, and sieving structures are tailored
to exploit these differences.
Arrays with nanoscale step heights
fractionate protein samples based on size.
Flow-counterbalanced capillary electrophoresis uses periodic pressure-driven
backflow to generate uneven EOF at a micro- and nanofluidic channel
junction to execute charge-based separations with significantly reduced
generates high flow velocities for high-speed chromatographic separations
of two fluorescent molecules in nanochannels.
Zeptomole concentrations of nonfluorescent dye molecules
are chromatographically separated in a nanofluidic channels and detected
by differential interference contrast thermal lens microscopy (DIC-TLM).
Molecules are selectively transported through intrinsic defects
in graphene by pressure and diffusion and filtered by size.
Voltage-tuned nanopores are modeled with Brownian
dynamics and are predicted to filter nanoparticles by altering the
local electric field within the pore.
Modeling also shows that nanochannels with finite EDLs and added
pressure-driven flow separate ions with the same electrophoretic mobility
but different valence.
modeling of nanoparticle separations through a nanopore shows that
EOF significantly impacts separation and can be tailored to make pores
permeable to only one type of particle.
Proteins are isolated at different ends of a nanochannel by concentration
gradient focusing, and theoretical data are in good agreement with
A sieving structure composed
of a nanoslit formed between a bowed
ridge and a coverslip is used for fast and continuous separation of
and DNA complexes.
Small analyte molecules pass through the nanoslit
unhindered, whereas larger molecules are trapped at the ridge and
must find alternative pathways. DNA is rapidly sieved with cylindrical
glass capillaries at high applied voltages.
The effects of ionic strength on the separation of single-stranded
and double-stranded DNA are probed in glass nanochannels.
Electrophoretic mobilities shift at different
ionic strengths, and the mobility difference between ss- and dsDNA
increases as ionic strength increases. DNA molecules of different
lengths are also separated in nanochannels with an asymmetric bipolar
Shorter molecules migrate completely
through the channel during the forward bias of the asymmetric pulse,
whereas longer molecules do not transit the entire channel and are
pulled back during the reverse bias. Simulations of Brownian dynamics
of DNA translocation through nanofilter arrays support experimental
results of variable pathways according to DNA length.
Small Volume Delivery/Manipulation
Handling of ultrasmall
volumes of liquid is critical to many analytical techniques. Nanofluidic
structures easily handle and store small sample volumes, and electrokinetic
transport can precisely manipulate attoliter-scale fluid volumes.
Liquid flow rates in the pL/min regime are
monitored in nanochannels by detection of electrochemically active
molecules with electrical cross-correlation spectroscopy.
A Laplace nanovalve generates 1.7 fL water
droplets in air, and these droplets are controlled in a nanochannel.
Nanopipets provide a straightforward
route to manipulate nano- to attoliter volumes of fluids. Electroosmotic
transport delivers small volumes of fluids from nanopipets, which
can be used to inject cells.
and delivery of molecules by nanopipets have been explored widely
for about a decade, but quantitative data of amounts dispensed are
lacking. A carbon ring/nanopore electrode at the tip of nanopipet
quantitatively estimates the amount of charged molecules delivered.
These studies reveal the impact (enhanced or
diminished delivery) of nanopipet surface charge on delivery of charged
molecules by electroosmosis. Finite element simulations and theoretical
studies determine the effects of pipet size, delivery voltage, pressure,
and distance to the underlying substrate on the spatial distribution
of delivered molecules.
the role of each parameter (pipet size, pressure and voltage, and
distance between probe and substrate) on delivery enables development
of a robust methodology for quantitative and localized drug delivery.
Fluid aspiration with nanopipets allows sampling and dispensing
of attoliter to picoliter volumes of fluid by application of voltage
across a liquid–liquid interface.
Changes in the surface tension at the interface, as a result of
application of voltage, generate forces sufficient to aspirate and
This method selectively
extracted mitochondrial DNA from single human BJ fibroblast cells,
and sequencing characterized the aspirated mitochondrial DNA. EOF
through nanopipets can also deposit and inject dyes
An electric field
generated between electrodes in each barrel of a theta pipet controls
the electromigration of charged microparticles between the two barrels
through a thin liquid meniscus between the substrate and pipet.
Substrate charge affects the deposition rate
of charged microparticles with higher deposition rates for surfaces
with like charge, and the pipet successfully delivered particles inside
individual Zea mays root hair cells.
Several types of electrochemical
reactions are monitored by nanofluidic devices.
Electrolysis of water is conducted experimentally in nanochannels
and theoretically modeled.
intensity of pH-dependent fluorescein tracks production of H2. Figure 5a–d shows annular
embedded in nanocapillary arrays that act as working electrodes for
delivery is enhanced by EOF, and conversion efficiency in these nanoarrays
is an order of magnitude greater than in microscale structures. Simulations
of transport in these nanoband arrays predict that transport of reacted
species away from the reaction site is much faster in nanochannels
than in microchannels due to rapid diffusion away from the center
of the nanopore.
of bound proteins are determined from the transport rate of ferricyanide
through protein-modified PAA nanochannels at different pH levels.
Electrochemical reactions conducted in nanofluidic devices
increased efficiency and enable single-particle reactions. (a–d)
Nanoscale ring-disk electrodes fabricated by FIB milling exhibit enhanced
molecular transport and current density compared to microscale devices.
Reprinted from ref (241). Copyright 2013 American Chemical Society. (e) Nanogap transducers
act as stochastic sensors and have sufficient gain to track the reduction
of single particles. Reprinted from ref (238). Copyright 2011 American Chemical Society.
(f) Single-molecule events measured in nanogap transducers are detected
as discrete current steps. Reprinted from ref (240). Copyright 2013 American
Chemical Society. (g) Nanoscale droplets formed at an electrode–surface
interface act as electrochemical cells to measure the electrocatalytic
activity of single gold nanoparticles. Reprinted from ref (247). Copyright 2012 American
platforms provide a method to study and
understand the response of a molecule to a particular environment
without perturbation from adjacent molecules.
To study single molecules in nanofluidic structures, a
small number of molecules are trapped in a nanogap between parallel
electrodes (Figure 5e)
to measure the oxidation and reduction of redox molecules
rapidly diffuse between the two electrodes and are subjected to multiple
cycles of oxidation and reduction to achieve the desired current amplification.
This technique was first used to study single
molecules by an electrochemical method,
and the same concept was adopted by several groups, who employ more
well-defined designs with parallel electrodes
and nanofluidic channels.
Simulations looked at the noise associated with redox-sensors
and determined that concentration fluctuations and adsorption contribute
to observed noise effects.
Nanopipets use a similar
strategy to confine a small number of molecules or particles in a
small gap. The liquid meniscus formed between a nanopipet and a conductive
substrate behaves like a small electrochemical cell (the area of the
electrode is a few micrometers squared). Confinement of a small number
of particles enables investigation of the electrocatalytic activity
of individual gold nanoparticles.
Figure 5g shows a schematic of meniscus formation at the
pipet-surface interface and a typical i–V curve for a single gold nanoparticle on
Nanopipets with tip diameters
<100 nm (Figure 1e) can be used as electrospray
emitters and coupled to a mass spectrometer.
The resulting mass spectra exhibit a number of interesting features
such as a reduced number of charged states for all of the large analytes
and a shift toward peaks with higher charged states, which may be
a consequence of formation of droplets having high surface charge
density. Further, samples sprayed from nanopipets have a greater signal-to-noise
ratio compared to samples sprayed from commercial pico-tips. Detailed
characterization of the nanopipet tips before and after ESI confirms
the robustness of these tips under ESI conditions. This methodology
is particularly attractive for imaging studies that make use of the
small tip size.
Nanofluidics has experienced
significant growth in the past two
decades, driven primarily by fundamental studies of physical forces
in nanoscale conduits and a better understanding how these forces
uniquely impact ion and fluid transport at the nanoscale. Interest
in nanofluidics continues to grow with improved fabrication techniques
that generate even smaller critical dimensions with higher precision
and repeatability. Future work with nanofluidic devices will include
fundamental studies of nanoscale transport to improve device performance
and application of nanofluidic devices to a wider range of analytical
problems. Of particular interest is the prospect of nanopore devices
to sequence DNA, which has, and will continue to be, a top priority
in nanofluidic research.
To achieve these goals, fundamental
challenges facing nanofluidic
research must be addressed, despite the recent introduction of commercially
available sequencing devices.
A major challenge
facing the field of nanofluidics is the lack of high-throughput, cost-effective
nanofabrication techniques with high device-to-device reproducibility.
Fabrication and testing of these devices are typically confined to
academic laboratories because expensive equipment and significant
fabrication time make scaled-up production of commercial instruments
difficult. In addition to fabrication constraints, most nanofluidic
devices require sophisticated support electronics with sufficient
current amplification and noise reduction to achieve high signal-to-noise
ratios for the analytes of interest. Engineering devices with quiet,
high-speed electronics and fast data analysis will be an important
next step to transition nanofluidic devices from the laboratory to
everyday use. Despite these limitations, nanofluidic research will
continue to expand our understanding of fundamental transport phenomena
and improve analytical methods.