Review

[Link]/CR

Nano-Bioelectronics
Anqi Zhang† and Charles M. Lieber*,†,‡
†
Department of Chemistry and Chemical Biology and ‡Harvard John A. Paulson School of Engineering and Applied Sciences,
Harvard University, Cambridge, Massachusetts 02138, United States

ABSTRACT: Nano-bioelectronics represents a rapidly expanding interdisciplinary field

that combines nanomaterials with biology and electronics and, in so doing, offers the
potential to overcome existing challenges in bioelectronics. In particular, shrinking
electronic transducer dimensions to the nanoscale and making their properties appear
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more biological can yield significant improvements in the sensitivity and

biocompatibility and thereby open up opportunities in fundamental biology and
healthcare. This review emphasizes recent advances in nano-bioelectronics enabled with
semiconductor nanostructures, including silicon nanowires, carbon nanotubes, and
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graphene. First, the synthesis and electrical properties of these nanomaterials are
discussed in the context of bioelectronics. Second, affinity-based nano-bioelectronic
sensors for highly sensitive analysis of biomolecules are reviewed. In these studies,
semiconductor nanostructures as transistor-based biosensors are discussed from
fundamental device behavior through sensing applications and future challenges.
Third, the complex interface between nanoelectronics and living biological systems,
from single cells to live animals, is reviewed. This discussion focuses on representative advances in electrophysiology enabled
using semiconductor nanostructures and their nanoelectronic devices for cellular measurements through emerging work where
arrays of nanoelectronic devices are incorporated within three-dimensional cell networks that define synthetic and natural tissues.
Last, some challenges and exciting future opportunities are discussed.

CONTENTS 3.3. Graphene Biosensors 231

3.3.1. Surface Chemistry and Functionaliza-
1. Introduction 216 tion 231
2. Nanostructure Building Blocks and Nanotransis- 3.3.2. Detection of Biological Species 232
tors 216 3.4. Prospects for Nanoelectronic Biosensors 232
2.1. Silicon Nanowires 216 4. Nanoelectronics−Cell Interfaces and Electrophy-
2.1.1. Basic Structures and Preparation 217 siological Recording 232
2.1.2. Advanced Morphologies and Structures 217 4.1. Traditional Extracellular Electrophysiological
2.1.3. Large-Scale Assembly of Nanowires 219 Recording 233
2.1.4. Nanowire Field-Effect Transistors 220 4.1.1. Principles of Extracellular Recording 233
2.2. Carbon Nanotubes 221 4.1.2. Passive Metallic Microelectrodes and
2.2.1. Structures, Preparation, and Assembly 221 Their Scaling Limits 233
2.2.2. Carbon Nanotube Field-Effect Transis- 4.1.3. Active Transistor Electrodes 233
tors 221 4.1.4. Extracellular Electrode−Cell Interfaces 233
2.3. Graphene 222 4.2. Nanowire Transistors for Extracellular Re-
2.3.1. Exfoliation of Graphite 222 cording 233
2.3.2. Synthesis of Graphene 223 4.2.1. Extracellular Recording from Cultured
2.3.3. Graphene Field-Effect Transistors 224 Neurons 233
3. Nanoelectronic Biosensors 224 4.2.2. Extracellular Recording from Cultured
3.1. Nanowire Biosensors 224 Cardiac Cells 233
3.1.1. Functional Principles of FET Sensors 225 4.2.3. Extracellular Recording of Other Electro-
3.1.2. Protein Detection 225 genic Cells 235
3.1.3. Nucleic Acid Detection 226 4.3. Graphene Transistors for Extracellular Re-
3.1.4. Virus Detection 227 cording 235
3.1.5. Methods for Enhancing the Sensitivity 4.4. Intracellular and Intracellular-like Electro-
of Nanowire Sensors 227 physiological Recording 235
3.2. Carbon Nanotube Biosensors 230
3.2.1. Surface Chemistry and Functionaliza-
tion 230 Received: October 12, 2015
3.2.2. Detection of Biological Species 231 Published: December 21, 2015

© 2015 American Chemical Society 215 DOI: 10.1021/[Link].5b00608

Chem. Rev. 2016, 116, 215−257
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4.4.1. Strengths and Constraints of Intracellu- electrogenic cells, such as neurons or cardiomyocytes, can
lar Measurements 235 record and/or stimulate bioelectrical activities in the cells or
4.4.2. Intracellular-like Recording with Pro- corresponding tissues (e.g., brain, heart, or muscle), by
truding Metal Electrodes 236 interconverting ionic and electronic currents at the device−
4.4.3. Intracellular 3D Nanowire Transistors 236 cell interface.17−20
4.4.4. Intracellular MEA-Based Nanopillars 237 The central element in a nano-bioelectronic device is the
5. Nanoelectronics−Tissue Interfaces and Electro- nanostructure that is used to sensitively record or stimulate a
physiological Recording 238 biological event of interest. The potential of nanostructures in
5.1. Acute Brain Slice Studies with Nanowire biology lies inherently in their small sizes and high surface-to-
Transistors 238 volume ratios. First, their high surface-to-volume ratio offers
5.2. Cardiac Tissue Studies with Nanowire Tran- high sensitivity to surface processes. Only a small number of
sistors 238 analyte molecules are needed to produce a measurable electrical
5.3. Cardiac Tissue Studies with Graphene signal, which allows both a reduction of sample volumes and
Transistors 239 the miniaturization of biosensors. In addition, the size scale of
5.4. 3D Nano-Bioelectronic Hybrids 241 nanostructures can be comparable to biological building blocks,
5.5. Injectable Electronics 242 such as proteins and nucleic acids, offering new ways to perturb
6. Conclusions 242 living systems from subcellular to tissue levels. The similar size
Author Information 243 scale of nanostructures and biological building blocks can also
Corresponding Author 243 facilitate seamless integration of nanoelectronics with cells and
Notes 243 tissues and enables unique opportunities in synthetic tissues
Biographies 243 and biomedical prosthetics.21−24
Acknowledgments 244 This review is organized to emphasize recent advances in
References 244 nano-bioelectronics enabled with semiconductor nanostruc-
tructures, including silicon nanowires (SiNWs), carbon nano-
tubes (CNTs), and graphene. We will briefly discuss the
1. INTRODUCTION relevant synthesis and electrical properties of these nanoma-
Bioelectronics can be broadly defined as the merger of terials in the context of bioelectronics in Section 2. Section 3
electronics with biological systems, where a bioelectronic discusses affinity-based nano-biosensors for highly sensitive
device transduces signals from the biological system to electrical analysis of biomolecules. In these studies, semiconductor
signals at the bio−electronics interface. The development of nanostructures have been utilized as the central element of
bioelectronics has resulted in vital biomedical devices, such as transistor-based biosensors. Sections 4 and 5 describe the
blood glucose sensors,1−3 cardiac pacemakers, and deep-brain complex interface between nanoelectronics and biological
stimulators.4,5 Despite the success of these devices, it should be systems, from single cell to in vivo live animal levels. Our
recognized that the electronic transducers have had substantial discussion will be focused on several representative conceptual
size mismatch with the biological systems to which the advances in electrophysiology enabled by using semiconductor
electronics were interfaced. Hence, substantially shrinking the nanostructures and their nanoelectronic devices, rather than
electronic transducer dimensions and making their properties trying to comprehensively cover all the work performed in this
appear more biological could lead to significant improvements vibrant field.
in the sensitivity and biocompatibility of next-generation
bioelectronics and thereby enhance and/or open up new 2. NANOSTRUCTURE BUILDING BLOCKS AND
opportunities in fundamental biology and healthcare areas.6,7 NANOTRANSISTORS
In this regard, a variety of nanomaterials, including zero- Nanostructure building blocks can be synthesized via the
dimensional (0D) nanoparticles, one-dimensional (1D) nano- bottom-up paradigm, in a manner that mimics how complex
tubes and nanowires, and two-dimensional (2D) nanosheets, biological systems are constructed by proteins and other
have emerged over the past several decades, with substantial biological building blocks in nature. Central to the bottom-up
progress made on their chemical synthesis, processing, and approach is the synthesis of building blocks with controlled
characterization.8−12 One motivation underlying these efforts structure, size, and morphologies, as these characteristics
has been to elucidate how the size, structure, and composition, determine their chemical and physical properties.8−10,12,25
for example, of such nanostructures lead to novel electronic, Bioelectronic devices based on these building blocks can be
optical, and magnetic properties, including quantum confine- rationally designed to exploit the unique properties of different
ment regime in one or more dimensions. The enhanced and nanomaterials with the goal of providing unique capabilities of
even unprecedented physical properties of such nanomaterials interfacing to and studying different biological systems. Thus,
offer potentially unique opportunities in biology. we will provide a brief introduction to the structure,
In particular, nano-bioelectronics represents a rapidly preparation, and electrical properties of three representative
expanding interdisciplinary field that combines nanomaterials semiconductor nanomaterials being used in bioelectronic
and nanoscience with biology and electronics and, in so doing, devices: silicon nanowires, carbon nanotubes, and graphene.
offers the potential to overcome existing challenges in We refer the interested reader to more comprehensive reviews
bioelectronics and to open up new frontiers. For example, an focused on the synthesis and properties of semiconductor
affinity-based biosensor, such as a protein or DNA sensor, nanowires,8,9,26−28 nanotubes,25,29−33 and graphene.34−38
utilizes a surface-immobilized recognition probe to selectively
interact with the biological analyte in solution and yields a 2.1. Silicon Nanowires
electrical signal directly proportional to analyte concentra- We will focus on SiNWs as a representative example of
tion.13−16 In addition, bioelectronic devices interfaced to semiconducting NWs for bioelectronics since their key
216 DOI: 10.1021/[Link].5b00608
Chem. Rev. 2016, 116, 215−257
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nanostructure properties, including morphology, size, compo-

sition and doping, have been widely explored and can now be
precisely controlled during synthesis.26−28 Silicon and other
NWs also can be well-aligned into highly ordered arrays,39−44
which are important for the construction of arrays of
bioelectronic devices and integrated circuits. Also, the diameter
of NWs can be readily reduced to a few nanometers,45 and the
crystalline structure and smooth surface of chemically
synthesized NWs reduce scattering and result in enhanced
electrical properties.46 Thus, semiconductor NWs represent a
logical pathway to scaling of semiconductor devices for
potentially novel bioelectronic devices.
Figure 1. VLS growth mechanism of SiNWs.
2.1.1. Basic Structures and Preparation. The basic
SiNW has a uniform composition, 1D structure with diameter
typically in the range between 3 and 500 nm and length ranging the 1D crystal growth begins via the transfer of the
from several hundreds of nanometers to millimeters.47 The two semiconductor material from the vapor reactant at the
paradigms for realizing SiNWs can be categorized as top-down vapor−liquid interface into the eutectic, followed by atom
and bottom-up.26,28,48−53 The top-down paradigm, often based (e.g., Si atoms) addition at the liquid−solid interface. In
on lithography, deposition, and etching steps, offers convenient addition, because the gold nanoparticle remains at the tip of the
processing of a uniform macroscopic section of material, such NW during VLS growth, it can define the diameter of the 1D
as a Si wafer, into different predefined structures with nanoscale NW as long as all reactant addition is through the liquid−solid
dimensions. The bottom-up paradigm, on the other hand, is interface.
based on synthesizing target architectures from individual Following the initial laser ablation studies, the nanoparticle-
atoms and molecules, with key nanometer-scale metrics built in catalyzed VLS process was expanded to exploit more controlled
through synthesis and/or subsequent assembly, thus enabling reactant sources, such as chemical vapor deposition
the potential to go beyond the limits of top-down technologies. (CVD).57,70 In this modification, a volatile gaseous precursor,
The bottom-up approach can lead to entirely new device such as SiH4 or SiCl4, was used as the silicon source for the
concepts and functional systems54 and thereby create growth of SiNWs. The gaseous precursor is transported by a
technologies that people have not yet imagined. The bottom- carrier gas, typically argon or hydrogen, to the surface of the
up synthesis of SiNWs has been primarily achieved by vapor- metal catalyst, where the precursor reacts and is decomposed.
phase growth.51,55−67 Among these, the nanoparticle-catalyzed Because of the excellent control over many aspects of the
vapor−liquid−solid (VLS) mechanism8 is the most widely used synthesis process, CVD−VLS growth has become arguably the
because of its simplicity and versatility. most powerful option for NW synthesis.
In 1964, Wagner and Ellis68 introduced the VLS growth of During VLS growth, SiNWs are formed in near-equilibrium
silicon structures, where the VLS mechanism underpins most of condition, and the growth processes can thus be considered
the bottom-up synthetic studies of SiNWs. It is important to primarily thermodynamically driven. As a result, the preferred
recognize, however, that this early work yielded only micro- growth direction is the one that minimizes the total free energy.
scopic Si whiskers or wires. Truly nanoscopic SiNWs were not Wu et al.45 and Schmidt et al.71 found that the growth
reported until 199769 and 1998,55,56 when research groups at directions of intrinsic SiNWs can be influenced by the diameter
Harvard University55,69 and Hong Kong City University56 of the NWs. The larger intrinsic SiNWs with diameters above
reported nanoscale SiNWs. In the former work,55,69 laser 20 nm exhibit a dominant ⟨111⟩ growth direction, whereas
ablation was used to generate nanoscale catalysts and NWs with smaller diameters (3−10 nm) tend to grow along
simultaneously silicon or germanium reactant and thereby the ⟨110⟩ direction, and ⟨112⟩ NWs are obtained in the
yield high-quality single crystalline silicon and germanium NWs transition region. These results can be understood by the
by the now general and widely used nanocluster-catalyzed VLS increasing contribution of the silicon/vacuum surface energy to
growth approach. In the latter study,56 a distinct oxide-catalyzed the total free energy in smaller NWs. In addition, system
NW growth mechanism was proposed. These early demon- pressure during growth and doping level can play an important
strations opened up substantial opportunities in this exciting role in determining NW growth orientations27,72,73 and
field, and significant progress since has been achieved on length represents an area for further study in the future.
scales ranging from the atomic and up, in controlling the 2.1.2. Advanced Morphologies and Structures. An
morphology, size, composition, and doping of SiNWs.8−10,26−28 important feature of the bottom-up growth paradigm is the
Key points in the VLS mechanism are illustrated in Figure 1, capability for tunable synthesis of new materials and
in which a nanometer-scale catalyst is used to promote the architectures on many length scales. In this regard, 1D
material growth constrained along only one direction. In this semiconductor NWs represent one of the most powerful
mechanism, a metal catalyst, such as a gold (Au) nanoparticle, platforms for rationally designed synthetic realization of
forms a liquid metal−semiconductor eutectic alloy at an complex nanostructure building blocks or systems with
elevated temperature by adsorbing the vapor reactant, such as predictable physical and chemical properties. In addition,
silane (SiH4) or silane decomposition products. Continuous assembly of distinct functional SiNW building blocks can
incorporation of the semiconductor material in the alloy enable exploration and applications of multicomponent devices
through the vapor−liquid interface ultimately results in and integrated systems. To date, five general structural classes
supersaturation of the semiconductor material. It then drives have been demonstrated: homogeneous NWs, axial modulated
the precipitation of the semiconductor material at the liquid− structures, radial/coaxial modulated structures, branched/tree-
solid interface to achieve minimum free energy. Accordingly, like NWs, and kinked structures (Figure 2).74−120 As discussed
217 DOI: 10.1021/[Link].5b00608
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[Link]. Radial NW Heterostructures. Radial core/shell NW

structures can be achieved by the deposition of the shell on the
surface of the 1D NW core. One of the first reports of core−
shell NW heterostructures by Lauhon et al. used a CVD
approach to grow homo- and heterostructures from Si and Ge,
with different dopant concentrations, including i-Si/p-Si, Si/Ge
and Ge/Si core−shell NWs.87 Later, the Lieber group reported
CVD growth of (InGaN/GaN)n quantum wells,88,89 regiose-
lective NW shell synthesis in studies of Ge and Si growth on
faceted SiNW surfaces,90 and facet-selective growth of CdS on
Figure 2. Five classes of NW structures available today: basic (center), SiNWs.91 Recently, Plateau−Rayleigh crystal growth of periodic
axial, core/shell, branched and kinked structures, clockwise from lower shells on NWs has been demonstrated with tunable
left. Reprinted with permission from ref 6. Copyright 2011 Materials morphological features, such as diameter-modulation perio-
Research Society. dicity and amplitude and cross sectional anisotropy.92
[Link]. Branched NW Heterostructures.93 A third basic
motif involves the synthesis of branched or treelike NWs. The
below, several of these modulated nanowire structures, which
higher degree of complexity in such structures increases the
have not been achieved in carbon-based materials, offer unique
potential for NW applications, by increasing the number of
advantages for creating nano-bioelectronic interfaces.
[Link]. Axial NW Heterostructures.74,75 The controlled connection points and by providing a means for parallel
synthesis of axial NW superlattices was reported in 2002 by connectivity and interconnection of functional elements.
three research groups, representing a significant step in the Several methods have been reported for the synthesis of
controlled synthesis of NW heterostructures.76−79 As an branched structures, ranging from sequential catalyst-assisted
example, Gudiksen et al. successfully synthesized GaAs/GaP, growth,94−102 solution growth on existing NWs,103−106 phase-
n-Si/p-Si, and n-InP/p-InP axial NW heterostructures.79 The transition-induced branching,107−110 one-step self-catalytic
prerequisite for the synthesis of axial NW heterostructures is growth,111−114 and screw-dislocation-driven growth.115−118 As
the continuation of the NW elongation when different vapor an example, Jiang et al. reported the synthesis of branched NW
phase reactants are introduced, and thus, the metal catalyst structures, including groups IV, III−V, and II−VI, with metal
should be able to promote reactions with all of these reactants branches selectively grown on core or core−shell NW
under similar growth conditions. This seminal work on axial- backbones.101 As the branched NWs are obtained by dispersion
modulated NWs was subsequently expanded with the synthesis of catalysts on the backbone and reintroduction of the growth
of metal−semiconductor junctions,80,81 doping-modulated precursors for a second growth stage, each generation of NW
NWs,82,83 as well as NWs with ultrashort morphology branches can have a unique diameter and composition.
features.84,85 In a recent work, the Tian group showed that [Link]. Kinked NW Structures. The VLS growth mechanism
pressure-dependent formation of etchant-resistant patterns can be further extended to the stereocontrolled synthesis of
within SiNWs by iterated deposition−diffusion-incorporation kinked NWs. Tian et al. showed that kinks can be created by
of gold (originated from the nanoparticle catalyst) to yield introducing a perturbation, such as purging and reintroducing
mesostructured SiNWs after etching.86 reactants, during the normal NW growth.73 The kinks consist

Figure 3. (a) Schematic for flow-assisted alignment of parallel NW arrays. (b, c) Schematic and SEM images of crossed NW matrix obtained by
changing the flow direction sequentially. (d) A triangle of NWs obtained in a three-step assembly process. Reprinted with permission from ref 122.
Copyright 2001 American Association for the Advancement of Science. (e) Contact printing of NWs. (f) 3D NW circuit fabricated by multiple
contact printing steps. Reprinted with permission from ref 160. Copyright 2007 American Chemical Society.

218 DOI: 10.1021/[Link].5b00608

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Figure 4. (a) Schematics of the nanocombing process. (b, c) SEM images of SiNWs on the combing surface. Reprinted with permission from ref
167. Copyright 2013 Nature Publishing Group.

of two straight single-crystalline arms connected by one fixed ing/electrostatic interactions,138−143 interface-induced assem-
120° joint in a SiNW. In addition, nanoscale axial p−n bly,144,145 electric/magnetic field-assisted alignment,146−154
junctions can be synthetically introduced at the joints of kinked PDMS transfer,155−159 contact/roll printing techniques,160−166
SiNWs.119 The stereochemistry of adjacent kinks can be and nanocombing,167 as well as other assembly methods.168−172
controlled,54,120 which allows the synthesis of increasingly As an early example, Huang et al. designed a flow-assisted
complex 2D and 3D structures with unique capabilities for technique by combining fluidic alignment with surface-
bioelectronics. patterning, whereby the separation and spatial location of
The design and rational synthesis of the complex NWs NW arrays are readily controlled.122 In this method, NWs are
described above render them unique building blocks for aligned by passing a suspension of NWs through microfluidic
controlling nano−bio interfaces. For example, kinked NW channel structures formed between a polydimethylsiloxane
structures, which will be discussed further below, can improve (PDMS) mold and a flat substrate, prefunctionalized to
cell/device junction tightness, and with phospholipid bilayer enhance the interaction with NWs (Figure 3a,b). Alternating
coatings, these nanoscale transistors can function as pointlike,
the flow in orthogonal directions in a two-step assembly
mechanically noninvasive probes capable of entering cells
process yielded crossbar structures (Figure 3c), while equi-
without the need for direct exchange of solution (as occurs with
lateral triangles were assembled in a three-layer deposition
patch pipettes).54 In addition, recent studies of mesostructured
sequence using 60° angles between the three flow directions
SiNWs can enhance the nano−bio interfaces86 and thus could
contribute to nano-bioelectronic devices in the future as well. (Figure 3d). In 2007, Javey et al. developed a contact-printing
2.1.3. Large-Scale Assembly of Nanowires. NWs method to directly transfer NWs from a growth substrate to a
synthesized by bottom-up approaches often have random second device substrate.160 As illustrated in Figure 3e, the NW
alignment and orientations and thus cannot be used “as is” for growth substrate is placed upside down on top of a
fabrication of ordered device arrays. To fulfill the potential of lithographically patterned substrate and translated horizontally
NWs as building blocks for such applications requires effective for several millimeters under normal load to transfer the as-
assembly and integration techniques that transfer NWs from grown NWs onto the underlying substrate with an orientation
growth substrates onto the device substrates with control of parallel to the sliding direction. This NW transfer process can
alignment and position.39−44 Reported methods include flow- be repeated multiple times, along with the deposition of a thin
assisted alignment,121−126 the Langmuir−Blodgett techni- SiO2 insulating layer between adjacent NW layers to yield 3D
que,127−135 the blown bubble method,136,137 chemical bind- stacked arrays (Figure 3f).
219 DOI: 10.1021/[Link].5b00608
Chem. Rev. 2016, 116, 215−257
Chemical Reviews Review

In 2013, a dry-transfer approach based on an innovative the substrate. The gate electrode is capacitively coupled to the
nanoscale “combing” technique was developed.167 A small semiconductor channel by an insulating oxide layer. If no gate
anchoring region is opened in the accepting substrate where the voltage (Vg) is applied (the “off” state), the FET is equivalent to
tips of the NWs attach due to strong attractive forces. This two p−n junctions connected back-to-back with almost no
anchoring allows subsequent substrate translation to comb the current flows. In the “on” state, when Vg exceeds a threshold
NWs over the polymer-protected region of the device voltage, charge carriers (e.g., holes for p-Si and electrons for n-
substrates. Significantly, large-area arrays of parallel NWs with Si) are induced at the semiconductor−oxide interface, and the
<1° misalignment and with >98.5% yield are produced. This potential barrier of the channel drops, resulting in a significant
order of magnitude improvement in alignment has enabled tunneling current flow. Therefore, the conductance of the
fabrication and demonstration of the largest integrated NW semiconductor channel between the source and drain regions
circuit by the bottom-up approach (Figure 4). can be switched from off to on and modulated in the on-state
These approaches show clearly the capability of realizing by the potential at the gate electrode.
postgrowth bottom-up assembly of distinct NW materials into Similar to its planar counterpart, the basic electronic
single- and multilayer arrays of NW-based nanoelectronic properties of a semiconductor NW can be characterized using
devices, which are especially important for enabling multiplexed electrical transport studies in a FET (NW FET) configuration
measurements at cell/tissue levels with subcellular resolu- (Figure 5b).175 For example, NWs can be deposited on the
tion.21−24,173,174 For example and as will be discussed in more surface of a silicon wafer covered with an oxidized layer (Si/
detail below, arrays of NW FET devices fabricated on substrates SiO2), in which the underlying conducting silicon can serve as a
have been used for high-resolution recording from acute brain global back gate. The naturally grown oxide layer on SiNWs
slices,173 while arrays incorporated into free-standing macro- can be used as the gate oxide. Source and drain electrodes are
porous meshlike structures have opened completely new areas defined by lithography followed by evaporation of metal
of tissue engineering, where the nanoelectronic mesh serves as contacts. The electrostatic potential of the NWs is tuned by Vg,
a scaffold to electronically innervate synthetic tissue in 3D,21,22 which modulates the carrier concentration and conductance of
as well as novel injectable nanoelectronics capable of in vivo the NW. Comprehensive reviews focused on NW FETs can be
brain mapping.23,24,174 consulted for further details.46,176
2.1.4. Nanowire Field-Effect Transistors. The field-effect In the case of NWs with homogeneous structure and
transistor (FET) is a fundamental building block of high- composition, SiNWs have been extensively studied, due to the
density integrated circuits. In a standard planar FET (Figure dominance of silicon in the semiconductor industry. Nonethe-
5a), the semiconductor substrate (e.g., p-Si) is connected to the less, the initial transport studies of SiNWs were far from
gate (G), source (S), and drain (D) electrodes. The source and optimal, due to the large sample-to-sample variation and low
drain regions, through which current is injected and collected, carrier mobility. Improved control during synthesis, including
respectively, have an opposite doping (e.g., n-type) to that of the NW diameter down to <20 nm and fine-tuned doping level
and electrical properties, has contributed to important advances
and NW devices approaching 1D quantum confinement that
are desirable for high-performance FETs,55 such as p- and n-
channel SiNW FETs.135,177−179 Still, these NW FETs are
Schottky barrier devices and their performances are affected by
the metal contact (S and D), unlike conventional metal oxide−
semiconductor FET (MOSFETs) with degenerately doped
semiconductor source/drain contacts. Annealing is a general
method to effectively form ohmic contacts and increase the on-
current.
Parallel integration of p-SiNW devices was subsequently
demonstrated by a combination of Langmuir−Blodgett (LB)
assembly and photolithography techniques.135 From the
electrical characterization of randomly chosen NW devices
within large arrays (Figure 5c), both linear source−drain
current (Isd) versus source−drain voltage (Vsd) curves and
saturation at larger negative voltages were obtained, as expected
for p-type FETs. Furthermore, Zheng et al. demonstrated the
first example of controlled growth of n-type SiNWs with
tunable phosphorus doping and fabrication of high-perform-
ance n-type NW FETs.179 The Ids−Vds curves recorded with
Figure 5. (a) A typical planar FET. The semiconductor substrate (e.g., gate voltage (Vgs) from −5 to 5 V are linear from small values
p-Si) is connected to gate (G), source (S), and drain (D) electrodes of Vds, saturated at Vds ∼ 2 V, and show increases (decreases) in
and can be switches between the “off” and “on” states by applying the conductance as Vgs becomes more positive (negative), as
Vg. (b) Schematic and SEM image of a NW FET. Reprinted with expected for an n-channel FET (Figure 5d). Ohmic-like
permission from ref 175. Copyright 2002 American Chemical Society.
(c, d) Transistor characteristics of p- and n-type NWs. Insets show
contacts with lower source contact resistance (Rs) were
transfer characteristics of the back-gated devices. (c) Reprinted with obtained with heavily doped NWs, while the non-ohmic
permission from ref 135. Copyright 2004 American Chemical Society. contacts with higher Rs were observed for lightly doped NWs,
(d) Reprinted with permission from ref 179. Copyright 2004 John where the dopant-concentration-dependent Rs limits the
Wiley & Sons, Inc. measured transconductance.
220 DOI: 10.1021/[Link].5b00608
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Chemical Reviews Review

Koo et al. also reported the fabrication of dual-gated SiNW SWNTs degrade the performance of the devices. Methods to
FETs, having both a top metal gate and a backside substrate overcome this challenge, including growth control and
gate.180 A conducting channel of either accumulated holes or postgrowth separation, have been explored.225,226 In growth-
inversion electrons is formed by the back gate, which also based separation of SWNTs, both introducing a weak oxidative
controls the shape of the Schottky barrier between the channel gas227−230 or applying an external field231,232 have been
and the source/drain electrodes. The top gate then can control reported. For example, Ding et al. demonstrated the growth
ambipolar conduction (either hole or electron conduction of SWNT arrays on quartz substrate using an ethanol/methanol
occurs depending on the gate bias) in these SiNW FETs. mixture as the carbon source and reported that >95% of the
Enhanced channel conductance modulation could be achieved nanotubes were semiconducting.227 The authors found that this
with these dual-gated SiNW devices. selective growth is achieved due to the presence of methanol
In addition to homogeneous NWs, axial heterostruc- and a strong affinity between nanotubes and the quartz
tures,80,181 radial heterostructures,182−185 and crossed-NW substrate. In addition, a number of postgrowth separation
structures157,160,186−188 have also been developed to extend methods of s-/m-SWNTs, including electrical breakdown,233,234
the versatility of NW FETs. For example, Colinge et al. gas etching,235−237 electromagnetic radiation,238−240 interaction
reported junctionless NW FETs, in which the current flows with other molecules,35,241 and centrifugation,242 have been
through the bulk of the channel, rather than just along its studied.
surface.189 Compared to classical transistors, these NW devices Ultimately, control of the diameter and chirality of SWNTs is
exhibit low leakage currents, near-ideal subthreshold slope, and needed to a priori determine electronic properties, as is possible
less mobility degradation with gate voltage and temperature. with NWs. Reported strategies to control chirality have
2.2. Carbon Nanotubes included growth rate dependence,243,244 catalyst and gas
interactions,245−248 and cap engineering.249−253 Recently, the
CNTs have large aspect ratios, high mechanical strength, Li group used tungsten-based bimetallic alloy nanoparticles of
excellent chemical and thermal stability, and rich electronic and noncubic symmetry as the catalysts for CNT growth with
optical properties.29,30,190−192 Applications of CNTs span many reported control of diameter and chirality.248 The tungsten-
fields, including composite materials, nanoelectronics, and based catalysts have high melting points and are able to
energy storage.193−198 In recent years, efforts have also been maintain their crystal structure during the CVD process and,
devoted to exploring the potential biological applications of consequently, to regulate the chirality and diameter of the as-
CNTs.199−202 grown SWNTs (Figure 6a). Specifically, they found semi-
2.2.1. Structures, Preparation, and Assembly. CNTs conducting (12,6) SWNTs were synthesized at an abundance
are rolled up, seamless cylinders of graphene sheets. CNTs are of >92% (Figure 6b,c). Experimental evidence and theoretical
classified as single-walled nanotubes (SWNTs) or multiwalled simulations reveal that the good structural match between the
nanotubes (MWNTs), depending on the number of their carbon atom arrangement around the nanotube circumference
concentric walls.190,203 The diameters of SWNTs and MWNTs and the arrangement of the atoms in one of the planes of the
are typically 0.4−2 and 2−100 nm, respectively, and their nanocrystal catalyst facilitates the (n,m) preferential growth of
lengths range from hundreds of nanometers to centimeters. SWNTs. Alternatively, Sanchez-Valencia et al. used surface-
The chirality of SWNTs, which is the angle with which the catalyzed cyclodehydrogenation to convert a molecular
graphene sheets roll up with respect to lattice vectors, precursor into ultrashort, singly capped (6,6) “armchair”
determines their electronic properties.190 The chiral vector nanotube seeds on a platinum (111) surface. Single-chirality
(n,m) is used to quantify this rolling up angle, where n and m and essentially defect-free SWNTs were then synthesized by
are the integer numbers of hexagons traversed in the two unit- elongation of these seeds, achieving lengths up to a few
vector directions of the graphene lattice. This vector can be hundred nanometers (Figure 6d).253 The ability to directly
directly related to the electronic properties of SWNTs. produce large amounts of nearly identical SWNTs opens new
Specifically, a SWNT will be metallic if (n − m) is a multiple opportunities for CNTs in integrated electronics.
of 3 and a semiconductor otherwise. Statistically, one-third are As 1D nanostructures, CNTs, similar to SiNWs, also need to
metallic and two-thirds are semiconducting.204 For FETs, be assembled for many applications. Two major strategies for
semiconducting SWNTs are required. producing CNT arrays include postsynthesis assembly254,255
A number of techniques have been used to produce and the aligned growth.206,256−258 Postsynthesis assembly
CNTs,205−208 including high-temperature arc-discharge, laser approaches, which are similar to the assembly methods for
ablation, and solar-beam-induced vaporization209−215 and low- SiNWs, include flow-directed alignment,259−265 Langmuir−
temperature216−224 methods such as CVD. The first reported Blodgett assembly,266,267 electric-field-268−270 and magnetic-
SWNTs were prepared using a carbon arc-discharge method field-directed271−274 alignment, mechanical shearing,275−280 or
with metal catalyst mixed in one of the carbon electrodes.210 blown bubble film techniques.136,281 On the other hand, in situ
Despite its simplicity, this method is capable of producing growth approach produces aligned CNTs during growth using
structurally pristine SWNTs with a relatively high yield. CVD controlled CVD processes, including gas-flow-directed
was first used to grow CNTs in 1993 by incorporating growth,282−290 external-field-directed growth,232,291,292 and
nanoparticles on substrates with hydrocarbon gas as the surface-directed growth.25,293−297 These in situ aligned growth
reactant.216 Substantial efforts have been placed on CVD methods have the advantage of avoiding defects induced during
synthesis of CNTs, and it is now undoubtedly the preferred postassembly and can be combined with the standard
method for synthesizing SWNTs of highest structural quality fabrication of silicon-based devices.
and has been extensively reviewed.31−33 2.2.2. Carbon Nanotube Field-Effect Transistors.
One big challenge for directly using SWNTs for FET devices Semiconducting SWNTs can be used as the channel material
is that the as-synthesized SWNTs are always a mixture of for FETs, as first demonstrated by the Dekker group.298 Many
semiconducting (s-) and metallic (m-) tubes, while the latter m- research groups have demonstrated the potential of SWNTs as
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metal contacts depends sensitively on the fabrication quality

during contact evaporation and annealing.
Although individual SWNTs can possess very good
electronic properties, it has been difficult to integrate these
building blocks into large-scale electronics, due in part to their
low current output per nanotube, small active areas, and the
aforementioned heterogeneous mixtures of metallic and
semiconducting as-synthesized tubes. This heterogeneity in
electronic properties is one major difference between SWNTs
and SiNWs, where the mixture of s-/m-SWNTs will yield
device-to-device performance variations.
2.3. Graphene
Graphene is defined as a single 2D layer of sp2-hybridized
carbon atoms joined by covalent bonds to form a flat hexagonal
lattice with excellent electrical and mechanical properties.
Below we will provide a brief summary of the preparation of
graphene and graphene device properties; readers are referred
to reviews of graphene synthesis and properties of graphene
FETs for more detailed information.34,36−38,315−317
2.3.1. Exfoliation of Graphite. Graphite consists of many
sheets of graphene stacked together. In a single graphene sheet,
carbon atoms are linked by covalent bonds, while adjacent
graphene sheets interact by much weaker van der Waals bonds.
Therefore, single graphene sheets can be obtained by
exfoliating graphite. Reported exfoliation methods include
mechanical, liquid, and oxidation/reduction processes.
The experimental isolation of single-layer graphene was first
demonstrated by Geim and co-workers at Manchester
University318 (Figure 7a). They used a mechanical exfoliation
technique (i.e., peeling with adhesive tape) to isolate graphene
from graphite and obtained single- and few-layer flakes pinned
to the receiver substrate, by van der Waals forces. Graphene
flakes prepared by mechanical exfoliation have high crystal
quality and can be more than 100 μm2 in size. The pristine
graphene prepared by mechanical exfoliation exhibits remark-
ably high carrier mobility, room temperature Hall effect, and
ambipolar field-effect characteristics.319−321 The high carrier
mobility and ambipolar device characteristics are valuable for
bioelectronics. However, mechanical exfoliation is of low
throughput and not able to produce large graphene sheets.
Figure 6. Schemes for synthesis of SWNTs with single chirality. (a) These drawbacks have limited the use of mechanically
Preparation of the W−Co catalyst and the growth of a SWNT. (b) exfoliated graphene to primarily single-device studies.
UV−vis−NIR spectrum from 42 samples. (c) Relative abundances of Another exfoliation process is achieved in liquid assisted by
various chiralities from ∼3300 nanotubes. Reprinted with permission ultrasonication,322,323 as the solvent−graphene interaction is
from ref 248. Copyright 2014 Nature Publishing Group. (d) balanced by the intersheet attractive forces after exfoliation.
Formation of singly capped ultrashort (6,6) seed and subsequent Solvents with surface tension ∼40 mJ m−2 are most suitable for
elongation of SWNT. Reprinted with permission from ref 253.
Copyright 2014 Nature Publishing Group.
graphene dispersion because they minimize the interfacial
tension.324 For example, Hernandez et al. obtained graphene
dispersions with concentrations up to ∼0.01 mg mL−1 in
organic solvents such as N-methylpyrrolidone (NMP). In the
building blocks in applications such as displays, flexible same year, Blake et al. achieved graphite exfoliation by
electronics, and printable electronics.255,257 Due to their 1D sonication in dimethylformamide (DMF).325 Bourlinos et al.
transport and long mean free path, SWNTs can enable ballistic proposed perfluorinated aromatic solvents and tested their
transport in short-channel devices.299 It has been shown that exfoliating performance.326 Qian et al. produced monolayer and
SWNTs can have high mobility and current-carrying bilayer graphene by a solvothermal-assisted exfoliation process
capacity.300,301 Due to oxygen doping in air, semiconducting in acetonitrile, and the yield reached 10−12 wt %.327 Small
SWNTs show p-type behavior. Several approaches have been organic molecules and polymers can further promote the
reported to convert them to n-type, including chemical exfoliation of graphite, especially when they have a good
doping,302−306 annealing,303,307 and metal contact engineer- adsorption on graphene sheets.328−337 For instance, Dai and co-
ing.308−310 It has been found that the performance of a SWNT workers inserted tetrabutylammonium hydroxide (TBA) into
FET depends dramatically on the work functions of the contact oleum-intercalated graphite and sonicated it in a DMF solution
metals,298,299,311−314 and the interface between SWNTs and of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-
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Figure 7. (a) A mechanically exfoliated single-layer graphene sheet. Reprinted with permission from ref 318. Copyright 2004 American Association
for the Advancement of Science. (b) Liquid-phase exfoliated two-layer graphene LB film on quartz. (c) Transparency spectra of one- (black), two-
(red), and three-layer (green) LB films. Reprinted with permission from ref 333. Copyright 2008 Nature Publishing Group. (d) Large-area graphene
grown by CVD on copper substrate spanning 30 in. diagonally. Reprinted with permission from ref 365. Copyright 2010 Nature Publishing Group.
(e) AFM image of epitaxial graphene grown on SiC. Reprinted with permission from ref 370. Copyright 2009 Nature Publishing Group. (f) STM
image of synthesized graphene nanoribbons. Reprinted with permission from ref 373. Copyright 2010 Nature Publishing Group.

[methoxy(polyethylene glycol)-5000] (DSPE−mPEG) to form 2.3.2. Synthesis of Graphene. An alternative to the top-
a homogeneous suspension.333 The resulted graphene sheets down exfoliation processes is bottom-up CVD synthesis of
are made into conducting films by Langmuir−Blodgett graphene.352−354 The CVD method relies on the catalytic and
assembly on transparent substrates. The one-, two- and three- carbon-saturated properties of the specific metals upon
layer films on quartz afforded transparencies of ∼93, 88, and exposure to a hydrocarbon gas at high temperatures. At first,
83%, respectively (Figure 7b,c). The scalability of liquid-phase graphene grown by CVD was reported using Ni and Cu
exfoliation can be used to deposit graphene on different substrates,355−359 and subsequently, this work was extended to
substrates that are not applicable to mechanical cleavage. other transition-metal substrates.360−364 Specifically, heating a
Nonetheless, the exfoliated graphene obtained from sonication Ni substrate in the presence of hydrocarbon leads to
often has a large variety of flakes consisting of a different decomposition and dissolution of the carbon in Ni. Because
number of layers, and the electronic properties of the graphene carbon atoms have very different solubility in Ni at high and
can also be affected by the surfactants and/or polymers used in low temperatures, as the substrate is cooled down, carbon
the exfoliation processes. atoms diffuse to the Ni surface and form graphene films. It is
A third and perhaps the oldest method involves oxidizing important to note that graphene grown on Ni is polycrystalline
graphite to expand its graphitic layers, followed by exfoliation and usually consists of single-layer and few-layer to multilayer
regions. On the other hand, Cu allows higher-quality single-
into single layers of graphene oxide (GO) and finally reduction
layer graphene growth. This phenomenon is due to the fact that
to remove the oxygen groups. Three approaches have been
carbon has a relatively low solubility in Cu, and only a small
used to oxidize graphite: the Brodie,338 Staudenmeier,339 and
percentage of carbon atoms are dissolved in the substrate.
Hummers340 methods. In 2010, Marcano et al. improved the
Single- or double-layered graphene is realized during the
Hummers method to obtain a larger fraction of hydrophilic cooling process. Bae et al. demonstrated that the monolayer
oxidized graphene material.341 After oxidation, the van der graphene films grown by CVD on Cu substrates can be as large
Waals force between the layers is weakened, and the interlayer as 30 in. (Figure 7d).365 For electronic applications of
spacing increases from 0.34 nm in graphite to above 0.6 nm. As graphene, the catalytic metal substrate needs to be removed
a result, single GO flakes can be isolated by ultrasonication. and the graphene is transferred onto other substrates. One
Many methods have been used to remove oxygen groups from approach involves etching the metal substrate while the
the GO structure and restore the desired sp2-hybridized graphene is supported by an inert polymer, such as poly(methyl
structure, such as chemical,342−346 thermal,347−349 and electro- methacrylate) (PMMA) or PDMS, followed by transfer of the
chemical350,351 treatments. Nonetheless, the oxygen functional polymer/graphene onto the desired substrate.358,366 The
groups cannot be completely removed by these reduction physical properties of CVD-grown graphene deviate to some
procedures. Significantly, the residual oxygen functional groups extent from those of pristine graphene formed by mechanical
and oxidation-created defects reduce or eliminate most of the exfoliation, due to lattice defects and impurities. Furthermore,
unique electronic properties of pristine graphene in reduced the necessity of transferring the as-grown graphene film from
GO materials. the metal growth substrate to an insulating substrate for device
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Figure 8. Schematic comparison of (top) a standard FET device and (bottom) a SiNW FET sensor. The NW surface is functionalized with a
receptor layer to recognize target biomolecules in a solution, which are charged and provide a molecular gating effect on SiNWs. Reprinted with
permission from ref 397. Copyright 2006 Future Medicine Ltd.

fabrication further introduces additional defects and impurities 3. NANOELECTRONIC BIOSENSORS

that can degrade the electrical and mechanical performances of Next-generation biomedical diagnostics demand novel bio-
the CVD graphene. sensors and assays that can fulfill the requirements of
Another method to synthesize uniform, wafer-size graphene ultrasensitivity and high-throughput. Many semiconducting
layers involves epitaxial growth on single-crystalline silicon nanomaterials, such as NWs, SWNTs, and graphene, have
carbide (SiC) substrates that are heated in vacuum to high been studied for the electronic sensing in an effort to address
temperatures. As Si sublimes faster than carbon from SiC, the these needs. Due to their unique structural and chemical
excess carbon atoms remaining behind on the surface can characteristics, including diameters similar to biomolecules,
rearrange to form graphene layers (Figure 7e).367−371 None- high surface-to-volume ratios, and tailorable surfaces, these
theless, the high cost of single crystal SiC wafers precludes nanomaterials can be fabricated as high-performance FETs
large-scale growth of graphene using this approach. Last, suitable for label-free, real-time, sensitive detection of proteins
coupling of polycyclic aromatic molecules on metal surface and other biomolecules.387
represents another route to produce nanoscale graphene The electrical detection of biomolecules using a nanomateri-
(Figure 7f).372−375 al-based FET (nanoFET) can be understood as follows. The
2.3.3. Graphene Field-Effect Transistors. Theoretical surface of a nanoFET is functionalized with biomolecule
predictions have long suggested extremely high carrier mobility receptors, such as monoclonal antibodies or single-strand DNA
in graphene due to the high quality of its 2D crystal lattice. In (ssDNA) probes, which can selectively bind to biomolecule
2008, the Kim group measured a carrier mobility in excess of targets in solution. The binding of charged biomolecules (the
200 000 cm2 V−1 s−1 in suspended graphene with minimized sign and quantities of the charges depend on the isoelectric
substrate-induced scattering.376 This high carrier mobility point of the biomolecules and the solution pH) leads to a
implies that charge transport is essentially ballistic on the variation of charge or electric potential at the nanoFET surface,
micrometer scale, even at room temperature. These results have in a way similar to applying an external potential to gate
generated significant interest in graphene as a possible material electrode in a conventional FET device. The charge carrier
for the next-generation semiconductor devices. density of the nanoFET is thus tuned and leads to an electrical
Graphene FETs can exhibit an ambipolar field effect. Due to conductivity change associated with biomolecular binding
its ultrahigh mobility, graphene FETs respond quickly to events in real time. Due to the similar diameter or thickness
variations of gate-source voltage. However, the absence of a to most biomolecules (e.g., proteins and nucleic acids), these
band gap yields a small on/off ratio in graphene FETs, which binding events can be sensitively detected by the nanoFETs.
has hindered applications of this material in semiconducting Furthermore, incorporation of a number of these nanoFETs in
electronics. Several approaches have been proposed to a single device array functionalized with different surface
overcome this limitation by creating a band gap in graphene receptors can allow for multiplexed electrical detection in the
through (i) application of uniaxial strain,377,378 (ii) using bilayer same assay, enabling a unique and powerful platform for
graphene under an external field,379−382 and (iii) employing chemical/biological recognition.
quantum-confined nanoribbons with well-defined edges.383−386 In this section, we will introduce NW-, SWNT-, and
For the application of biosensing, three different structures of graphene-based FET biosensors, with an emphasis on SiNWs,
graphene FETs have been developed: (1) back-gated graphene which represent the first nanoFET biosensors reported.388
FETs, where the graphene film is transferred or deposited on a Representative examples in which FET sensors are applied to
dielectric surface (typically a SiO2 layer) and source/drain detect chemical and biomolecule targets, including proteins,
electrodes are fabricated on the top; (2) top-gated graphene nucleic acids, and viruses, are summarized. Furthermore,
FETs, where the gate dielectric is prepared on the graphene methods for improving the sensitivity of nanoFET sensors
surface (this configuration has more flexibility in electronic are briefly illustrated.
applications but also suffers from lower carrier mobility because
the top gate induces scattering); and (3) dual-gated graphene 3.1. Nanowire Biosensors
FETs, where a conducting substrate acts as the back gate, a SiNWs have been extensively investigated for nanoelectronic
metal as the top gate, and graphene as the conducting channel sensing with great success. In 2001, Cui et al. reported the first
between the source and drain electrodes. demonstration of SiNW-based biosensors.388 Since then, SiNW
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Figure 9. (a) Schematic of a functionalized NW device and the protonation/deprotonation process that changes the surface charge state. (b)
Changes in NW conductance versus pH. Reprinted with permission from ref 388. Copyright 2001 American Association for the Advancement of
Science.

FET biosensors have been explored for detection of a variety of that enable the specific recognition of chemical/biological
biological species, including disease marker proteins,389−391 molecule targets. Covalent binding to the native silicon oxide
DNA mismatch identification,392−394 and single viruses.395 In (SiO2) layer that naturally grows on SiNWs represents one of
addition, SiNW FETs have also been used to study small the most robust approaches for probe attachment and takes
molecule−protein interactions,389,391,396 suggesting exciting advantage of the wealth of knowledge available from studies
potentials for drug screening, determination of reaction focused on functionalization of glass (SiO2) slides.402 A detailed
kinetics, and the inhibition of enzymatic activity. More SiNW surface functionalization protocol has been described
importantly, the capability of integrating hundreds of SiNW elsewhere.403 The simplest and earliest established example of
FETs into the same device array, each electrically addressable, this approach is hydrogen ion concentration detection or pH
has been robustly demonstrated, as a milestone for the sensing.388 In this case, the SiO2 layer at a p-SiNW surface is
biosensing applications from laboratory to clinics.15,397,398 modified with 3-aminopropyltriethoxysilane (APTES), which
3.1.1. Functional Principles of FET Sensors. The use of yields amino group (−NH2) termination on the NW surface
planar FETs for ion-selective sensors was introduced several (Figure 9a). The amino groups and silanol groups (Si−OH) on
decades ago,399 while their opportunities as chemical and the oxide layer undergo protonation and deprotonation as the
biological sensors have further been advanced in new and hydrogen ion concentration varies, thereby changing the
significant ways using nanomaterials. The scheme of planar surface charge and the NW conductance. The NW electrical
FET has been discussed in section 2.1.4. Here, we use NWs as conductance shows a stepwise, discrete, and stable increase, in
an example to show the sensing mechanism of these nanoFETs. response to pH values from 2 to 9 (Figure 9b). More recently,
Similar to planar FETs, the conductance of a NW FET can be Noy and co-workers demonstrated SiNW FETs modified with
controlled by variations in the charge density or electric lipid bilayers with and without ligand-gated and voltage-gated
potential at the channel region, making FETs ideal candidates ion channels to monitor the solution pH. With lipid bilayers
for chemical and biological sensing, as the electric field resulting containing ion channels, devices responded to changes in
from the binding of a charged molecule to the NW surface is solution pH, and when the channels were blocked, the device
analogous to applying a voltage via a gate electrode. In a p-type response was strongly diminished.404 Sensing studies of several
SiNW functionalized with surface receptors that can specifically distinct classes of biological targets are discussed below.
capture chemical/biomolecule targets, binding of molecules 3.1.2. Protein Detection. The sensitive detection of
with negative charges (similar to applying a negative gate proteins, especially those known as disease markers, offers
voltage) leads to accumulation of charge carriers (holes) and a substantial potential to benefit disease diagnosis and treatment.
corresponding increase in conductance (Figure 8). However, In 2001, pioneering work demonstrated real-time protein
binding of molecules with positive charges (similar to applying sensing with SiNW FET devices.388 Specifically, SiNWs
a positive gate voltage) will deplete holes and subsequently functionalized with biotin receptors were used to selectively
reduce the conductance. Hence, NW FETs enable real-time detect streptavidin at concentrations down to 10 pM,
label-free direct electrical readout of biological events, including substantially lower than other methods at the time. However,
binding/unbinding, enzymatic reactions, and electron transfer, strong binding affinity between biotin and streptavidin leads to
capabilities that are ideal for developing a platform to analyze irreversible binding and precluded monitoring unbinding and
biological samples. sequential measurements at different streptavidin concentra-
Semiconductor NWs composed of Si or other materials (e.g., tions. To overcome this limitation, several reversible surface
ZnO and In2O3) have been used for the development of FET modifications have been explored, including biotin−mono-
biosensors.388,400,401 Among them, the molecular-size diameter, clonal antibiotin binding and calmodulin (CaM)−Ca 2+
high electron or hole mobility, and versatile surface interaction, to investigate quantitative concentration-dependent
functionalization of SiNWs, as well as the potential of analyses.388 In a more recent study,391 CaM-modified SiNWs
interfacing with existing mature silicon industry processing, were used to detect Ca2+ and CaM-binding proteins through
have propelled these NWs to be one of the most widely studied the association/dissociation interaction between glutathione
for biomolecular sensing.387 SiNW FETs are transformed into and glutathione S-transferase. In addition, this basic approach
nanosensors by surface functionalization with probe molecules has been used to demonstrate successful concentration-
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Figure 10. (a) Optical image of a NW array. (b) Sequential detection of PSA, CEA, and mucin-1 solutions using three SiNW FET sensors. (c)
Complementary sensing of PSA using p-type (NW1) and n-type (NW2) SiNW FET sensors. Reprinted with permission from ref 389. Copyright
2005 Nature Publishing Group.

dependent detection of cardiac troponin T390 (a biomarker for Later, an anisotropic wet-etch fabrication method was
myocardial infarction), SARS virus nucleocapsid proteins,405 reported as an alternative “top-down” NW device fabrication
and bovine serum albumin406 in recent literature and thus strategy for NW FET sensors.409 The sensitivity of these top-
further validate the efficacy of NW FETs as protein sensors. down-fabricated SiNW devices were shown to have sensitivity
In genomics and proteomics research, simultaneous below 100 fM for biotin−streptavidin interaction, mouse
detection of multiple proteins is believed to be especially immunoglobulin G (IgG), and mouse immunoglobulin A
important for diagnosing complex diseases such as can- (IgA) detection.
cers.407,408 Moreover, the availability of different biomarkers 3.1.3. Nucleic Acid Detection. In addition to sensing
matched with different stages of diseases could allow for early protein binding/unbinding, real−time detection of nucleic acids
detection and robust diagnosis. The work described above (e.g., DNAs and RNAs) has been successfully carried out by Si
using SiNW FET devices,388 although powerful in detecting and GaN NW FET devices.392−394,410 The surface functional-
binding/unbinding of proteins, lacked the capability of selective ization methods and detection schemes are similar to those
multiplexed sensing. To address this key issue, Zheng et al. described above for protein sensing, where nucleic acid
developed integrated NW sensor arrays, in which ∼100 concentration is transduced following binding to a probe by
individually addressable NW FETs were functionalized with changes in device conductance. Multisegment CdTe−Au−
several different receptors in 2005 (Figure 10a), and CdTe NW are used in devices in which Au segments are
demonstrated several new sensing capabilities.389 Specifically, modified with thiol-terminated DNA probes and binding to
monoclonal antibodies for the cancer marker proteins prostate these probes induces a conductance change in the overall
specific antigen (PSA), carcinoembryonic antigen (CEA), and device structure.411
mucin-1 were used to functionalize SiNW FETs in the same A major difference between nucleic acid and protein
device array (Figure 10b). Upon addition of buffer solutions detection exists in the fact that the high density of negative
containing different concentrations of these cancer biomarkers, charges on the nucleic acid phosphate backbones requires high
changes in electrical conductance of the corresponding NW ionic strength buffers to screen the repulsion and to allow for
FETs were recorded with femtomolar sensitivity, which is binding when DNA or RNA is used as the probe molecule.
several orders of magnitude better than possible with the However, high ionic strength solutions have short Debye
standard enzyme-linked immunosorbent assay (ELISA).389 screening lengths (see section [Link]), which can make
This work also introduced the new concept of incorporating detection difficult or preclude it. A solution that overcomes
both p-type and n-type NWs into the same device array (Figure this high ionic strength binding/screening issue involves using
10c). In so doing, the binding of a negatively charged neutral charge peptide nucleic acids (PNAs),412,413 which
biomarker, such as PSA, on the NW sensor surfaces led to an exhibit excellent binding affinity with DNA at lower ionic
increase in conductance for p-SiNWs and a decrease for the n- strengths. Indeed, modification of SiNWs with PNA probe
SiNWs in the same sensor chip. These complementary, molecules was shown to exhibit time-dependent conductance
opposite electric signals can be used to distinguish false changes associated with selective binding of complementary
positive signals and enable real-time, highly sensitive, and target DNA at concentrations as low as 10 fM. Moreover, this
selective detection of multiplexed biomolecule targets. Sim- work showed that DNA biosensor could be used to distinguish
ilarly, Zhou and co-workers reported the complementary fully complementary (wild type) versus single-base mismatched
sensing of PSA using n-type In2O3 NWs and p-type (mutant) DNA targets associated with cystic fibrosis.392
SWNTs.400 The enhanced electrical conductance for the NW Additional studies using SiNWs functionalized with PNA
sensors and the suppressed electrical signal for the SWNT probes in which the DNA target binding domain distance was
sensors upon the PSA addition are demonstrated with changed exhibited a reduction in sensitivity with increasing
concentrations down to 5 ng/mL sensitivity at physiological distance between the hybridization site and the NW surface.414
buffer concentrations. This observation is consistent with the basic sensing
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mechanism, since the “field effect” is reduced for the fixed

charge as the separation from the SiNW surface increases.
Alternatively, electrostatic adsorption has also been utilized
for surface functionalization of SiNW devices used in DNA
detection.415 Bunimovich et al. reported electrostatic adsorp-
tion of primary DNA probe strands onto amine-terminated
SiNW surfaces, where the approximately parallel orientation of
the DNA probes along the NW surface reduces Debye
screening effects and can thereby yield sensitive DNA
detection.415
More recently, detection of other nucleic acid targets using
PNA-modified SiNWs has also been demonstrated. For
instance, microRNAs (miRNAs), which are a large class of
short, noncoding RNA molecules that regulate animal and plant
genomes, have been proposed as biomarkers for cancer
diagnosis.416 PNA-functionalized SiNW devices have shown
the capability to detect miRNAs down to a remarkable
sensitivity of 1 fM,417 ca. 1 order of magnitude better than
reported earlier for DNA detection.414 This phenomenon can
be attributed to the higher thermal stability and melting
temperature of PNA−RNA complex than that of PNA−DNA
complex. The technique enabled identification of fully
complementary versus one-base-mismatched miRNA sequen-
ces, as well as detection of miRNA in total RNA extracted from Figure 11. Schematic of virus binding/unbinding to a SiNW FET and
HeLa cells, and thus offers substantial potential as a new the corresponding time-dependent conductance change. Reprinted
diagnostic tool. with permission from ref 395. Copyright 2004 National Academy of
3.1.4. Virus Detection. Viruses are the major cause of Sciences of the United States of America.
infectious diseases, which remain the world’s leading cause of
death.418 Successful treatment of viral diseases often depends during synthesis, these rationally designed and synthesized
upon rapid and accurate identification of viruses at ultralow branched NWs provide well-controlled variations in the
concentrations. The first demonstration of a nanoFET-based composition of the NW backbone and branches and allow
virus sensor involved the detection of influenza A virus using for complex electronic and photonic nanodevices. For instance,
SiNW devices. By recording the corresponding electrical Jiang et al. developed the general synthesis of branched, single-
conductance changes upon binding/unbinding of virus particles crystalline semiconductor NW heterostructures, including Si
to monoclonal-antibody-modified SiNWs, the selective detec- backbones with Au branches.101 These Au-branched NW
tion of influenza A at the single-particle level was demon- devices were investigated as nanoelectronic sensors for
strated.395 The binding kinetics between different virus− biomolecular detection. The Au branches, which can be
receptor interactions was also electrically differentiated by modified in a highly specific manner, act as the receptor-
SiNW FETs (Figure 11). In addition, simultaneous detection of functionalized “antennas” for the biomolecule analyte and
influenza A and adenovirus using independent SiNW provide the potential to achieve enhanced capturing efficiency
biosensors functionalized with distinct antibodies for these and sensitivity through the 3D connectivity and interconnec-
two types of viruses was demonstrated,395 and more recently, tion. A sensitivity of 80 pg/mL for PSA detection was obtained
SiNW-FET-based selective detection of influenza A viruses from these mAb-modified p-Si/Au-branch NW FET sensors,
down to 29 viral particles per microliter was achieved for breath with high selectivity.
condensate samples.419 Both of these achievements represent [Link]. Detection in the Subthreshold Regime. The
important proof-of-concept steps toward powerful viral fundamental characteristics of NW FET devices, such as the
diagnostic devices. transconductance and noise, can have substantial effect on their
Another example of virus detection is the diagnosis of detection sensitivity. Conventionally, nanoFET-based sensors
dengue, a commonly prevalent arthropod-borne viral infec- are operated in the “on” state (above the threshold voltage),
tion.420 In this latter work, a specific nucleic acid fragment with where the transconductance depends linearly on gate-voltage or
69 base pairs derived from dengus serotype 2 virus genome surface potential. However, in the subthreshold regime, it is
sequence was selected as the target DNA and amplified by the well-known that the device conductance depends exponentially
reverse transcription polymerase chain reaction (RT-PCR). on gate voltage,421 which could in principle lead to much higher
The hybridization of the target DNA- and PNA-functionalized analyte binding sensitivity. Indeed, Gao et al. have studied and
SiNW FET sensors increases the device resistance, leading to a compared carefully the detection sensitivity of SiNW FET
sensitivity limit down to 10 fM. sensors in the linear and subthreshold regimes (Figure 12).422
3.1.5. Methods for Enhancing the Sensitivity of In previous literature using SiNW FET sensors,388 the
Nanowire Sensors. [Link]. 3D Branched Nanowires for conductance change (ΔG) or the resistance change (ΔR) of
Enhanced Efficiency in Analyte Capture. Three-dimensional the sensor devices was used to quantify the concentration of the
(3D) branched NWs,93−95,101,108,111 where secondary NW target molecules. However, an absolute signal change, such as
branches are grown in a radial direction from a primary NW ΔG, does not reflect the intrinsic device sensitivity, especially
backbone, provide the capability of achieving 3D connectivity. when working in the subthreshold regime, where device
By functionally encoding at well-defined branch junctions conductance is very small. To better compare sensing in
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Figure 12. (a) Conductance, G, vs Vg for a p-type SiNW FET. Inset: scheme for electrolyte gating. (b) Real-time pH sensing. The device in the
subthreshold regime shows much larger ΔG/G change versus pH. Reprinted with permission from ref 422. Copyright 2010 American Chemical
Society.

different device regimes, Gao et al. used a dimensionless sensors that involves incorporating a biomolecule-permeable
parameter, ΔG/G, to characterize and compare device polyethylene glycol (PEG) polymer layer on the FET sensor,
sensitivities. This principle is exemplified in both pH- and where the polymer increases the effective screening length near
protein-sensing experiments, where the electrolyte gating is the NW FET surface to allow for detection in high ionic
used to tune the operational mode of NW FETs (Figure 12b), strength solutions.427 Using PSA as a model system, they
thus suggesting that significant sensitivity enhancement can be showed that PEG-coated SiNW FETs can detect PSA in
achieved by optimization of the FET operating conditions and phosphate buffer concentrations up to 150 mM, with a
understanding the fundamental electrical gating property of detection sensitivity of ∼10 nM and linear response range up
NW FETs. One caveat to the success of this work is that the to 1000 nM. In contrast, similar FETs without PEG
device noise should be dominated by carrier−carrier scattering, functionalization can only detect PSA in buffer salt concen-
such that the noise is also exponentially reduced in the trations lower than 10 mM. This work suggests a new and
subthreshold regime. If the noise is dominated by other general device design strategy for the FET sensor applications
scattering mechanisms, such as contact current injection and/or in physiological environments, which is important for in vitro
interface trapping/detrapping, then it may not be possible to and in vivo biological sensing.
exploit the exponential dependence of conductance on gate [Link]. Electrokinetic Enhancement. Preconcentration by
voltage/surface potential in the subthreshold regime. electrokinetic manipulation of particles offers an advantageous
[Link]. Reducing the Debye Screening Effect. Conven- alternative approach for high-sensitivity protein detection.428 In
tional FET sensors detect the concentration of the target a nonuniform alternating current (AC) electric field, the
species by their intrinsic charge. The charges of solution-based dielectrophoresis (DEP) force can induce polarized particles to
molecules, however, can be screened by dissolved counterions move in a directed manner, leading to the formation of
in the solution. The Debye length, also known as the Debye concentration enhancement and depletion regions in a
radius, which is inversely proportional to the square root of the microfluidic flow channel. Compared to the detection limit
ionic strength of an electrolyte, represents the net or screened without AC excitation, NW sensors modified with monoclonal
electrostatic effect of a charged species in ionic solution. A high antibodies for PSA in an appropriate AC field exhibit close to a
ionic strength electrolyte solution leads to a short Debye ∼10 4 -fold increase in sensitivity; that is, the protein
length, and charges outside of the Debye length are electrically concentration at the sensor surface is increased by DEP. In
screened. For instance, the Debye length of 1× PBS, ∼0.7 nm, addition, NW devices functionalized with other receptors for
can screen most protein antigen charges when they bind to an capturing cholera toxin subunit B were also demonstrated,
antibody-modified FET surface. In order to reduce the charge suggesting the general applicability of this method for enhanced
screening effect of electrolyte solutions, the Debye length is sensitivity detection.
typically increased by using dilute buffer solutions with low ion [Link]. Frequency Domain Measurement. In addition to
concentrations.405,423 the conventional electrical measurement in real time,
Recently, several groups have reported approaches based on fluctuations in the NW FET electric signal at equilibrium can
smaller receptors, such as aptamers424 and antibody frag- convey additional information about the dynamics of the
ments,425 to reduce the distance between the FET surface and biomolecule−NW hybrid system through a coupling to carrier
biomolecule analyte being detected. These studies are transport in the device. For example, binding and unbinding
promising, although further studies are needed to determine can affect the intrinsic device noise and be characterized
how general detection is under the limit of physiological through measurements of the device noise spectra (Figure
conditions (Debye length <1 nm) as the sizes of the aptamer 13a).429 In a recent study, the noise spectra in frequency
and antibody fragment receptors are similar to or greater than domain was used to analyze contributions from different noise
this critical length scale. Kulkarni and Zhong also reported a sources.429 The frequency domain spectrum of a two-level
direct high-frequency measurement strategy for standard fluctuator system has the form of a Lorentzian function similar
biological receptors, although those measurement requires to that of a resistor−capacitor (RC) circuit (Figure 13b,c). The
significantly more complex device geometry, making difficult or 1/f noise is well-known in conventional metal-oxide semi-
precluding application to cellular and in vivo sensing.426 conductor FETs (MOSFETs) and arises from electron
Very recently, Lieber and co-workers developed a new and capture/emission from trap states.430,431 If biomolecule bind-
general strategy to overcome this challenge for NW FET ing/unbinding contributes substantially to the noise, it can
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membrane on which the SiNW FET nanopore devices are

fabricated. When the two chambers are filled with solutions of
different ionic strength, FET signals corresponding to DNA
translocation events can be recorded (Figure 14b,c). A 10−60
times higher signal is observed from the SiNW FET than that
of the corresponding ionic current change. This work
demonstrates a new nanopore sequencing device concept
with fast sequencing and large-scale integration properties.
[Link]. Double-Gate NW Sensors. In order to achieve high
sensitivity of NW FET sensors, extensive efforts have been
Figure 13. (a) Electrical noise in a time-domain measurement. (b) focused on advanced lithographic tools and size-reduction
Lorentzian and 1/f functions in the frequency domain. (c) Models of a techniques.434,435 For example, several groups have fabricated
two-level system (left) and RC circuit (right). Reprinted with and explored double-gate NW FET biosensor, with two
permission from ref 429. Copyright 2010 American Chemical Society. separated gates, G1 (primary) and G2 (secondary), straddling
both sidewalls of the SiNW, to enhance device sensitivity.434,435
leads to a Lorentzian peak in addition to the 1/f spectrum This work has shown that by applying the same voltage to G1
background. Frequency domain noise spectra of SiNW FETs and G2, the threshold voltage (VT) in the double-gate mode is
thus represents a means to study molecular binding kinetics and very sensitive to a small change of VG2 (the G2 voltage).
thermal fluctuations of the molecular layer on NW sensor Therefore, compared to a single-gate FET sensor, the sensing
surfaces. window of the double-gated FET is significantly broadened,
[Link]. NW−Nanopore Sensors. The integrated NW− especially in the subthreshold regime described earlier.
nanopore FET sensor has the potential for single-molecule [Link]. Detection of Biomolecules in Physiological Fluids.
DNA sequencing at low cost and with high throughput.432 The Rapid and accurate molecular analysis in physiological fluids
conventional nanopore DNA sequencing technique records (i.e., blood or serum) is essential for disease diagnosis and
ionic current from nanopores,433 while the NW−nanopore management. NW FET sensors, although powerful in ultra-
sensors allow for direct sequencing of DNA molecules with fast sensitive, real-time, multiplexed detection of multiple bio-
translocation rates given the much higher bandwidth of the NW molecular species, exhibit fundamental limitations regarding
FET. molecular sensing in complex, physiological solutions. As
Studies have shown that nanopores can be introduced discussed above in section [Link], the primary limitation to
adjacent to SiNW FETs using the focused electron beam in a FETs is related to the Debye screening effect436 in high ionic
transmission electron microscopy (TEM) (Figure 14a).432 A strength blood/serum samples.
sensor device can then be configured by attaching PDMS To overcome the limitation of the Debye length, researchers
solution reservoir chambers above and below the silicon nitride have developed methods to detect blood/serum samples in a

Figure 14. (a, b) Schematic and TEM image of a SiNW−nanopore sensor. (c) Recording of SiNW−nanopore FET conductance and ionic current
during DNA translocation. Reprinted with permission from ref 432. Copyright 2012 Nature Publishing Group.

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Figure 15. (a) Schematic of a polymer−biotin-functionalized SWNT FET for streptavidin recognition. (b) I−Vg relationship before and after adding
streptavidin. Reprinted with permission from ref 454. Copyright 2003 American Chemical Society.

controlled manner. One immediate method to reduce the ion small diameters can provide advantages versus traditional metal
concentration is to dilute the blood sample with a buffer electrodes. For more information on CNT electrochemical
solution.437 However, the diluting method has an impact on sensors, we refer readers to other reviews.441−445 Here, we will
ligand−protein and protein−protein interactions and also focus on SWNT FET biosensors446−450 composed of single
reduces the analyte concentration, which would raise the SWNTs or SWNT networks on SiO2/Si substrates with S/D
requirement for the device sensitivity instead. The second electrodes.
approach is to desalt the serum samples before the multiplex There have been a number of studies of SWNT FET
detection of biomarkers,389 although this might lead to a loss of biosensors, with four sensing mechanisms reported: (1)
target proteins during the desalting step. A third method electrostatic gating,451−453 (2) charge transfer,454 (3) scattering
involves introduction of a microfluidic purification chip (MPC) potential,455 and (4) Schottky barrier modification.456,457 The
system to preisolate the target molecules and release them into electrostatic mechanism involves gating of the SWNT by the
a pure buffer suitable for sensing, followed by the analysis using charged or polar analytes in a manner similar to the sensing
SiNW FET arrays438 in much the same manner as done with mechanism described for SiNWs or FET devices in general.
the desalting approach.389 The two-stage approach captures the
The second effect refers to charge transfer between the analytes
targets from a complex environment, such as a whole blood,
and the SWNT, which directly changes carrier concentration
and reduces sample consumption by effectively preconcentrat-
ing the biomarkers. A fourth method adopts a steady-state and conductance through the transfer (versus indirectly by
measurement instead of a real-time recording.439 Specifically, electrostatic gating). In the third mechanism, bound analytes
the resistance of the SiNW is measured in a low ionic strength act as a random scattering centers, which can reduce the carrier
buffer solution after antibody functionalization. Then, the mobility and SWNT conductivity. In the fourth mechanism,
SiNW sensor is incubated with undiluted serum and analytes change the current by modulating the Schottky barrier
subsequently washed to remove unbound proteins, followed height between SWNT−metal contacts. This latter mechanism
by the measurement of the second resistance value in the buffer requires non-ohmic contacts and also localizes sensing at the
solution. The concentration of the target molecules can be contact versus the SWNT material.
calculated according to the resistance change before and after 3.2.1. Surface Chemistry and Functionalization. Similar
antibody−antigen interaction. This method is independent of to SiNWs, SWNTs can be surface functionalized with different
the ionic strength of the sample solution, thus circumventing probes that are selective to molecular targets.458 Noncovalent
the Debye screening in physiological fluids. A final reported adsorption and covalent binding are two main approaches for
method uses small antibody fragments, which have been surface modification of SWNTs. Noncovalent functionalization
proposed to allow antigen binding to the NW surface within for SWNTs can be carried out by simple absorption of
the Debye length.425 In this approach, the sizes of antibody amphiphilic surfactant molecules or polymers. Since the sp2-
probes are reduced through common bioengineering methods, hybridized carbon network is not disrupted by noncovalent
and thus, both the signal transduction efficiency and the functionalization, the electrical properties of SWNTs are
detection capability can be improved. preserved.459 Supramolecular binding of aromatic molecules
The long-term stability of the SiNW nanoelectronic devices can be achieved by π−π stacking onto the SWNT polyaromatic
in physiological studies has also been investigated.440 Coated surface. For example, absorption by π−π stacking of pyrene
with a thin layer of Al2O3, SiNW FETs yield long-term stability derivatives has been widely utilized for noncovalent function-
(>4 months) in physiological model solutions at 37 °C. When alization of SWNTs, and the pyrene derivatives can be
coated with HfO2 as the surface protection layer, an even much covalently conjugated with antibodies and other biomole-
longer of stability of >1 year has been demonstrated by SiNW cules.460,461 In addition, ssDNAs can form a stable hybrid with
FETs in physiological model solutions. These latter results
SWNTs, where bases in the ssDNAs are believed to interact
suggest the potential of the SiNW FETs for long-term chronic
with SWNTs by π−π stacking.462,463
in vivo studies in animals and biomedical implants.
The hydrophobic nature of SWNT surfaces also represents a
3.2. Carbon Nanotube Biosensors challenge for biosensors, since this hydrophobicity can lead to
CNTs can be configured as either electrochemical or FET nonspecific adsorption of proteins and DNAs. Therefore,
sensors, where the latter are similar to NW-based FET surface passivation of SWNTs is required to prevent non-
biosensors discussed above. In the former case of electro- specific adsorption,464 while at the same time probe-target
chemical sensors, the CNTs are used as electrodes where their affinity and selectivity are maintained.
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Figure 16. (a) Conductance versus time monitoring various BSA concentrations. Reprinted with permission from ref 486. Copyright 2009 American
Chemical Society. (b) Schematic of a graphene FET device based on rGO for detection of IgG. IgG antibodies are anchored on AuNPs. Reprinted
with permission from ref 488. Copyright 2010 John Wiley & Sons, Inc. (c) Real-time detection of fibronection using the all-rGO sensor. Reprinted
with permission from ref 489. Copyright 2011 American Chemical Society.

3.2.2. Detection of Biological Species. In 2003, Dekker transfer and Schottky barrier modification, with Schottky
and co-workers reported the first single SWNT FET barrier modification being the dominant mechanism. To ensure
biosensor.465 The SWNTs were noncovalently modified with specific adsorption of DNA to SWNTs, Martinez et al. used the
glucose oxidase (GOx), which resulted in a conductance polymer poly(methyl methacrylate0.6-co-poly(ethylene glycol)-
decrease attributed to the capacitance change for the SWNT methacrylate0.15-co-N-succinimidyl methacrylate0.25) to modify
device. The conductance of the GOx-immobilized SWNTs also the SWNT surface via noncovalent bonding, with ssDNAs
showed a pH dependence consistent with the GOx protein bonded covalently to the polymer.468 In 2011, the Shepard
becoming more negative at higher pH values. Other researchers group covalently attached a ssDNA to a point defect on a
reported the use of SWNTs to detect biotin−streptavidin SWNT FET to study the kinetics and thermodynamics of DNA
binding (Figure 15).454 In this work, SWNTs were non- hybridization.469 Without the target DNA, a 1/f conductance
covalently modified with a layer of poly(ethylene imine) (PEI) noise is observed from the FET device. In a solution containing
and poly(ethylene glycol) (PEG), which was biotinylated and the target DNA, large-amplitude two-level fluctuations appear,
then used to detect binding of streptavidin to the biotin probes. with the signal-to-noise ratio better than 3 over the 1/f noise
Almost at the same time, Dai and co-workers reported studies background.
of SWNT devices modified with monoclonal antibodies for Furthermore, SWNT FETs have been used to detect small
detection of human autoantigen U1A.464 Using biotin− biomolecules470−473 and dynamics in living cells.474−477 For
streptavidin as a model, Hu et al. achieved protein detection example, Chen and co-workers showed that glycosylated
using SWNT networks modified with nonpolar groups (CH3) SWNT FETs can directly interface with PC12 cells by
and polar groups (NH3+).451 Later, Star and co-workers supporting cell adhesion and growth, and dynamic secretion
reported the use of SWNT FETs noncovalently functionalized of catecholamine resulted in current responses of the SWNT
with biotin for reversible detection of captavidin, a tyrosine FETs.
modified avidin.466 These devices show the capability of
3.3. Graphene Biosensors
differentiating two different biotin-binding molecules, strepta-
vidin and neutravidin, via the pH-dependent sensor response. Graphene FET based biosensors, which are similar to SWNT
Aside from protein detection, SWNT FETs have also been sensors and SiNW FET sensors described above, have also
applied for the detection of DNA hybridization. In 2006, Star et been extensively studied.38,478,479 An advantage of graphene
al. reported that SWNT networks modified with synthetic FETs in biosensing is that graphene has large surface-to-volume
probe oligonucleotides can specifically recognize target DNA ratio in a single device, although multi-SWNT and multi-NW
sequences,467 with a detection range from picomolar to devices will have similar characteristics.
micromolar concentrations. Later, Gui et al. reported that 3.3.1. Surface Chemistry and Functionalization. Similar
SWNT FETs immobilized with ssDNAs can differentiate to other nanoFETs sensors, it is necessary to functionalize the
complementary and single-base-mismatched DNA strands.457 graphene surface with recognition sites. The functionalization
The sensing response is attributed to a combination of charge strategies developed for SWNTs have been directly applied to
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graphene. Similar to SWNTs, direct covalent modification enzymes produce H2O2 molecules. As a strongly electron
strategies are not favorable for graphene functionalization, since withdrawing molecule, H2O2 acts as a p-dopant and increases
they alter the native lattice structure of graphene by converting the conductance of the p-type graphene biosensor. It was also
the carbon bonding from sp2 to sp3, which decreases the carrier shown that graphene outperforms thin-film network devices
mobility of graphene.480 Noncovalent modification based on made of SWNTs. In 2010, He et al. demonstrated that rGO
π−π stacking and hydrophobic interactions have been devices can be applied for the detection of dynamic secretion
successful and do not degrade substantially device perform- from living cells.491 The vesicular release of catecholamines
ance,478 as shown previously for related SWNT sensors. from cultured PC12 cells results in an increase in rGO
3.3.2. Detection of Biological Species. The first conductivity. In addition, graphene FETs are also effective in
graphene-based DNA biosensor was demonstrated by Mohanty detecting bacteria,481,492 viruses,493 and cells.494
and Berry in 2008 using GO devices.481 In this work, GO 3.4. Prospects for Nanoelectronic Biosensors
devices were covalently functionalized with ssDNA probes, and
when exposed to the target DNA, the hybridization process was More than one decade has passed since the first work reporting
detected through a change in conductivity. Later, Dong et al. nanoFET-based biosensors.388 Remarkable progress has been
reported detection of DNA hybridization with high specificity achieved since this time using all basic classes of nanomaterials,
using CVD-grown multilayer graphene, achieving a sensitivity as long as they have met the basic concept of a FET or FET-like
of 0.01 nM and the capability of identifying single base device originally described for these SiNW devices. The now
mismatches.482 They suggested that the signal is generated by broad range of examples described here show clearly both the
DNA-induced n-doping in graphene, instead of a field-effect. In robustness of the original concept and the potential of these
addition, the authors showed that decoration of Au nano- materials to significantly impact disease diagnosis, genetic
particles (AuNPs) increases the detection range since one screening, and drug discovery, as well as offering powerful new
AuNP can be covalently associated with multiple thiolated tools for research in many areas of disease diagnosis and life
probe ssDNAs to increase the loading efficiency and capacity. sciences.
Chen et al. used single-layer graphene FETs to achieve the Nonetheless, there are several areas of scientific study, which
DNA detection sensitivity down to 1 pM, which is more if addressed, could further push the limits of this technology for
sensitive than the multilayer graphene.483 To investigate the applications. First, one fundamental challenge to the ultra-
sensing mechanism of graphene FET DNA sensors, Lin et al. sensitive detection is to obtain well-defined receptor structures
measured the Hall effect and found that the hole carrier on nanodevice surfaces. In part, this reflects difficulties in
concentration of the graphene FETs increased with comple- characterizing receptor−device structure at the single nano-
mentary and single-base-mismatched DNA binding, although device level and correlating such results with sensing results.
the increase was less for the mismatched case.484 Recently, One approach that could address this structural issue at the
single device level would be by exploiting the substantial
ultrasensitive DNA detection using reduced GO (rGO) was
advances in cyro-EM,495,496 which could yield high-resolution
reported.485 In this report, rGO devices modified with PNA
structural information on the organic−biologic−nanodevice
probes exhibited a detection limit as low as 100 fM. This
interface. Another direction that could improve this critical
sensitivity is 1 order of magnitude lower than that of the
device−receptor interface would be through exploration of
previously reported graphene FET DNA biosensor based on
highly selective, self-limiting covalent chemistry that precisely
DNA−DNA hybridization. Moreover, the rGO FET biosensor
defines the distance and orientation of the receptors. Second,
is able to distinguish complementary DNA from one-base-
the real-time and multiplexed detection capabilities of nano-
mismatched DNA and noncomplementary DNA, in a manner
electronic FET sensors for direct analyses of whole blood/
shown much earlier with PNA-probe-modified SiNW FET
serum detection could yield important advances in clinical
sensors.392
monitoring and diagnostics. As discussed in sections [Link] and
Graphene biosensors have also been employed for the
[Link], the most critical issue has been overcoming Debye
detection of proteins. In 2009, Ohno et al. reported bovine
screening in physiological solutions. The new strategy of
serum albumin (BSA) detection using electrolyte-gated
modifying FET nanodevices with a permeable polymer layer to
graphene FETs.486 As shown in Figure 16a, the device
increase the effective screening length427 is one promising
conductance increases when negatively charged BSA is bound
strategy for achieving real-time detection, although further
to the graphene. In another work, the same group
fundamental studies will be necessary to develop this and/or
demonstrated an aptamer-modified graphene FETs for the
other approaches to the level of a technology. Third, almost all
detection of immunoglobulin E (IgE).487 Chen and co-workers
the nanoFET-based sensors are exclusively surface-bound
reported a graphene−AuNP hybrid sensor for protein
devices. For many applications, one of the most impactful
detection.488 Specifically, rGO sheets were modified with
directions could be the transformation from on-chip signaling
AuNPs and conjugated with anti-IgG antibodies (Figure to the in vivo monitoring as an implant. Recent advances in the
16b). In this case, the detection limit reaches ∼13 pM, development of NW FET arrays embedded in engineered tissue
among the best of the reported carbon-based protein sensors by patches,21 which could be implanted, and incorporation of
that time. In 2011, an all-rGO device was fabricated on a sensors in injectable electronics,23 which is directly implanted
transparent and flexible substrate489 and shown to detect in specific tissue, could enable the goal of direct in vivo
fibronectin at concentrations as low as 0.5 nM (Figure 16c). monitoring.
Graphene biosensors have been developed to detect other
biologically relevant species. Chen and co-workers used a
graphene sensor to detect glucose and glutamate, with a limit of 4. NANOELECTRONICS−CELL INTERFACES AND
detection (LOD) of 0.1 mM and 5 μM, respectively.490 The ELECTROPHYSIOLOGICAL RECORDING
detection is mediated by surface-functionalized glucose oxidase Electrophysiology is an important approach to investigate and
and glutamate dehydrogenase. The catalytic reactions by both understand bioelectrical activities in the body, including, but
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not limited to, the brain, heart, and muscles.497 For instance, electrodes, electrolyte−oxide−silicon field-effect transistors
neurons are the elementary processing units in the brain and (EOSFETs) and their arrays can be fabricated by standard
are organized and interconnected into complex networks. industrial complementary metal-oxide semiconductor (CMOS)
Information in neural networks is processed by the opening and technology, and they have been actively investigated for a
closing of ion channels on the membrane, producing action further improvement of signal detection capabilities in
potentials (APs) that propagate. Electrophysiological recording electrophysiological recording.
and decoding of the functional connectivity in the brain is 4.1.4. Extracellular Electrode−Cell Interfaces. The
central to basic neuroscience research. electrode−cell interface for passive and active electrodes plays
In addition, a variety of imaging techniques has been a central role in extracellular recording, since it affects the signal
developed for the purpose of brain mapping, such as magnetic amplitude and shape as well as noise levels. A general goal for
resonance imaging (MRI) and positron emission tomography improving the electrode−cell interface involves decreasing their
(PET).498−500 Although these noninvasive methods offer separation in order to increase the electrode−cell seal
coarse views, they cannot be used to analyze neuron networks. resistance.520 When neurons are cultured on a recording
To this end, many optical methods have emerged for both device, a gap or cleft exists between the electrode and cell
recording and stimulating signal propagation in neural membrane,528−530 where this cleft determines the seal
circuits. 501−506 However, optical approaches also have resistance. Methods to promote cell adhesion and reduce the
limitations, including difficulty in accessing deep brain activity cleft/increase seal resistance include surface modification,
and in obtaining simultaneously high spatial and temporal substrate modulation, and electrode shape control. For
resolution. Nano-bioelectronics has the potential to allow example, self-assembled monolayer-modified MEAs have been
multiplexed, long-term, and deep-brain detection of neural reported to significantly improve device performance.531−533
activity with a high spatiotemporal resolution. More generally, Surface-patterned MEAs have also been employed to
nanotechnology offers a number of opportunities for brain immobilize cultured neurons to enhance coupling.534,535 In
science.507−511 addition, studies of electrodes with 3D tips have been shown to
4.1. Traditional Extracellular Electrophysiological promote cell membrane wrapping around the tips, thus
Recording resulting in improved seal resistance compared to flat and
recessed electrodes.529,536
4.1.1. Principles of Extracellular Recording. An active
cellular process in electrogenic cells is accompanied by ionic 4.2. Nanowire Transistors for Extracellular Recording
current flows across the cell membrane, which change both the 4.2.1. Extracellular Recording from Cultured Neurons.
intracellular and extracellular potentials. A microelectrode The Lieber group first applied SiNW FETs for extracellular
positioned near to the outer membrane can in principle detect recording from cultured mammalian neurons in 2006.537 They
an extracellular potential change and is termed extracellular adopted a bottom-up paradigm to fabricate the SiNW FETs
recording. Two common recording paradigms are based on and passivated the arrays for cell culture. For example, they
passive metallic microelectrodes and active transistor electro- showed that polylysine patterning could promote the patterned
des. In the former case, the extracellular potential induces an growth of neuronal projections (axons and dendrites) over
interfacial electric current owing to the electrochemical arrays of four SiNW FETs (Figure 17a). At each point where
impedance, while for the latter, the extracellular potential acts the axon or dendrite crosses a NW device, a highly localized,
as a gate modulating the transistor conductance. In both cases, 0.01−0.02 μm2, synapse-like junction is formed, which allows
the output signal is closely related to the interface between cell for multisite recording with multiple SiNW FET devices from
and device. single neurons, in contrast to the typical one neuron per
4.1.2. Passive Metallic Microelectrodes and Their electrode achieved with MEAs and planar FETs.
Scaling Limits. In 1972, Thomas et al. described a planar This general approach was used to investigate action
multielectrode array for use in recording cultured cells.512 This potential spike propagation in several multiplexed SiNW
technique is now referred to as microelectrode arrays (MEAs) FET/neuron configurations. For example, in the above
and has been widely applied to record neural activity.513 In an configuration, one SiNW was used as a local input to elicit
MEA, each electrode is connected to a recording amplifier for action potential spikes that were recorded from two other
signal processing and has the potential to record single-unit SiNW devices with dendrite junctions, while the fourth SiNW,
activity. This capability makes MEAs a useful tool for the which is not interfaced with either an axon or dendrite, served
investigation of fast network dynamics both in vitro514−516 and as a control and showed no action potential signal (Figure
in vivo.517,518 In addition to recording signals from cells, MEAs 17b). In addition, SiNW/neuron configurations were designed
are also capable of stimulating them.519 A limiting feature of to investigate the spike propagation in axons and dendrites. As
conventional MEAs is the relatively large electrode sizes, 10−30 shown in Figure 17c, multiple SiNWs forming junctions with a
μm diameters, similar to or larger than the size of neuron soma. single dendrite and axon revealed signal propagation rates of
Reduction of the size of metal electrodes could increase their 0.16 m/s for the dendrite and 0.43 m/s for the axon. The
spatial resolution, but it also leads to an increase in impedance potential to extend this approach to highly integrated systems
that results in larger thermal noise and smaller recording was also shown with a configuration containing 50
amplitudes.520,521 To overcome this impedance limitation, independently addressable NW−axon elements for a single
surface modification methods to increase the electrode surface neuron (Figure 17d). Overall, these results showed early on the
area have been employed.522−525 potential for SiNW FET sensors to enable multiplexed
4.1.3. Active Transistor Electrodes. In 1991, Fromherz recording with subcellular spatial resolution from neurons.
and co-workers reported coupling and extracellular recording 4.2.2. Extracellular Recording from Cultured Cardiac
from neuron cells using planar Si FETs, 526 including Cells. Cardiomyocytes represent another electrogenic cell type
mammalian cells.527 As an alternative to metallic micro- that have been extensively studied with bioelectronic devices.
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Figure 18. Interfacing SiNW FETs with cardiomyocytes for

extracellular recording. (a) Long NWs fabricated by top-down
paradigm. Isolated cardiomyocytes are cultured on the NW chip,
where the dark lines denoted two NWs, I and II. (b) Currents
measured by NW I and II. A series of transient current events are
observed for NW II because it is covered by a contracting myocyte. (c)
Typical results from NW II (left) compared to the intracellular action
potential recorded with a nanopipette (right). Reprinted with
permission from ref 538. Copyright 2009 John Wiley & Sons, Inc.
(d, e) Schematic of a cardiomyocyte on a NW FET device and the
displacement (Z) of the PDMS/cell substrate. (f) Two traces recorded
with different Z values. Reprinted with permission from ref 539.
Figure 17. (a) Optical image of a NW−neuron interface. (b) Neuron Copyright 2009 National Academy of Sciences of the United States of
stimulation and resulting NW electrical responses. NW4 is not in America. (g) Pointlike recording using a short-channel NW fabricated
contact with any neurites. (c) Propagation studies using the multi- by the bottom-up paradigm. Left: Schematic of the short-channel
NW−neurite structures. Top: Optical image of the settings. Bottom: FET−cell interface, where the active channel size is comparable to that
Relation of latency time with distance and histogram of propagation of a few ion channels. Right: Typical signals of beating cardiomyocytes
speed. (d) Aligned axon crossing a 50-NW device array and from devices with channel lengths of 150 nm (blue), 80 nm (green),
corresponding signal propagation data. Reprinted with permission and 50 nm (red). Reprinted with permission from ref 84. Copyright
from ref 537. Copyright 2006 American Association for the 2012 American Chemical Society.
Advancement of Science.
upstroke current spike followed by a downstroke one. The
authors attributed the paired spikes to the onset and end of an
The groups of Chen538 and Lieber539 carried out extracellular AP, although this contrasts with most other work in the
recording for cardiac cells using SiNWs synthesized by top- literature.54,173,539,540 Specifically, typical extracellular record-
down and bottom-up approaches, respectively. An advantage of ings show only one peak associated with the rapid potential
top-down fabricated NWs is the capability to define (during change due to sodium ion channel opening.
fabrication) their length such that measurements across an Multiplexed measurements made with bottom-up SiNW
entire cell membrane or simultaneous measurement from FET device arrays interfaced with cultured embryonic chicken
multiple cells can be made (Figure 18a−c). After culturing cardiomyocytes show single biphasic peaks associated with each
cardiomyocytes on NW chips for 1−2 days, rhythmic transient action potential of the beating cells (Figure 18d−f). To
changes were observed in the device conductance, involving an investigate the signal propagation within cardiomyocyte
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monolayers, an average spacing between adjacent SiNW FETs ically exfoliated graphene FETs were interfaced to cultured
in the array is set around 300 μm. Multiple SiNW FETs in cardiomyocytes and showed well-defined extracellular signals
contact with cardiomyocytes are simultaneously recorded, with signal-to-noise ratios >4 (Figure 20a−c).544 An advantage
which show stable field potential spikes with high signal-to- of graphene FET devices is that the unique particle-hole
noise ratio (>10). The large signal magnitude indicates a good symmetry of graphene enables both n- and p-type recording
junction, and therefore, a large seal resistance exists between with the same device simply tuning the gate potential. This
SiNW FETs and cardiomyocytes. Later, the same group84 characteristic allows the origin of recorded spikes to be quickly
synthesized SiNW-encoded active FET channel lengths of 50, confirmed (if real versus artifact) by the spike phase flip across
80, and 150 nm (Figure 18g). These devices were interfaced to the Dirac point, as shown in Figure 20b. Quantitative
cardiomyocytes and the conductance−time response of action measurements (Figure 20c) showed a constant calibrated
potentials was recorded. Significantly, while the peak-to-peak extracellular voltage, ∼3.6 mV, at different water gate potentials,
voltage and signal-to-noise ratio showed little variation versus indicating a robust graphene−cell interface. Comparison of the
channel length, the deduced peak-to-peak extracellular action performances of graphene and NW FETs shows that graphene
potential width of ∼500 μs was found to be comparable to the FETs yield averaged action potential signals, while NW FETs
reported time constant for individual sodium ion channels. In yield higher resolution signals consistent with their smaller
longer or large devices, the extracellular action potential widths device size.
are typically ≥1 ms, presumably due to averaging over a In addition, Garrido and co-workers explored recording HL-
number of channels. These results thus suggest the possibility 1 cells using the CVD-grown p-type graphene devices (Figure
to monitor ion channel activity using short-channel NW FET 20d−f).545 In contrast to the uniform biphasic signals recorded
devices. In addition, Eschermann et al. evaluated the signal by exfoliated graphene devices,544 this work showed a variety of
shape recorded from the spontaneous activity of cardiac muscle peak shape, which can be attributed to variations in the cell−
HL-1 cells with SiNW transistors fabricated by the top-down graphene device junctions (Figure 20e,f). The multiplexed data
process.540 It is worth mentioning that they also used a (Figure 20f) also yielded signal propagation speeds of 12−28
diamond transistor array for recording HL-1 and HEK293 cells μm/ms, although the peak shape variation complicates this
transfected with potassium channels.541 analysis. More recently, Fang and co-workers demonstrated
4.2.3. Extracellular Recording of Other Electrogenic that suspended graphene FET devices can yield an optimal
Cells. SiNW FET devices have also been used to investigate configuration for cardiac extracellular recordings in terms of
electrophysiological properties of other types of electrogenic sensitivity and cell−device coupling. Moreover, their work
cells. For example, Chen and co-workers investigated the showed that the fluctuations of water ultimately set the
electrical activities of rat aortic smooth muscle cells (A7r5), as fundamental sensitivity limit of graphene-based bioelec-
shown in Figure 19,538 where each NW was in contact with tronics.546
4.4. Intracellular and Intracellular-like Electrophysiological
Recording
4.4.1. Strengths and Constraints of Intracellular
Measurements. In general, noninvasive extracellular record-
ing has advantages for long-term multiplexed measurements.
However, extracellular recording sacrifices the one-to-one
correspondence between cells and electrodes and also suffers
from other fundamental limitations, such as reduced signal
strength and quality and difficulty in recording subthreshold
Figure 19. SiNW interfaced to aortic smooth muscle cells. (a) Rat events.547 Intracellular recording can overcome all of these
aortic smooth muscle cells (A7r5) on the NW chip, in which the limitations, although not without other challenges. For example,
dashed square depicts the sensing area. (b) NW recorded current the patch-clamp methodology,548,549 which is the most widely
signals induced by membrane depolarizing in a high-concentration K+
used intracellular recording technique, requires the formation
solution. Reprinted with permission from ref 538. Copyright 2009
John Wiley & Sons, Inc. of direct ionic and/or electrical junctions between the probe tip
and the cytosol, which has several limitations. First, the probe
tip size needs to be within ∼0.2−5 μm: small enough to ensure
multiple cells. A series of current spikes were recorded by the penetrating the cell membrane without major damage but also
NW upon introduction of a solution containing a high large enough to produce a low junction impedance for
concentration of potassium ions with each spike having a recognizing small cellular signals. Second, irreversible changes
biphasic signal with durations of ∼1 ms similar to recording occur to the cell when it is directly exposed to external probe
from cardiomyocytes539,540 but nearly 2 orders of magnitude surfaces and electrolytes, thus limiting the capability for long-
shorter than that of typical intracellular action potential of A7r5 term recording. Third, the relatively large size of the pipettes
cells.542,543 As discussed above, this is consistent with the NWs and associated 3D manipulators limit potential integration for
recording the initial, rapid, inward sodium current, which multiplexed measurements. With these limitations in mind, it is
contributes to the initial depolarization of the action potential possible to define the characteristics of an ideal electronic
recorded with the patch clamp but not subsequent repolarizing device for intracellular recording; this device should possess (i)
steps. a small size to minimize invasiveness and potentially allow for
4.3. Graphene Transistors for Extracellular Recording direct contact with subcellular structures, (ii) high sensitivity
In comparison with 1D SiNW devices, graphene has a 2D flat and signal fidelity as size is decreased, and (iii) the capability to
structure similar to conventional Si FETs and planar micro- achieve multiplexed recording at both single cell and cell
electrodes used for cell electrophysiology. In 2010, mechan- network levels. Over the past several years, solid-state
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Figure 20. Extracellular recording using graphene FETs. (a) Schematic illustrating cardiomyocyte cell interfaced to graphene- and SiNW FET
devices. (b) Recorded extracellular spikes versus gate potential. (c) Summary of conductance change and calibrated voltage versus gate potential.
Reprinted with permission from ref 544. Copyright 2010 American Chemical Society. (d) Schematic of a cell on a graphene FET. (e) Typical two-
and one-sided peaks observed for different transistors. (f) Simultaneous current recordings from eight transistors in one FET array over hundreds of
milliseconds. Reprinted with permission from ref 545. Copyright 2011 John Wiley & Sons, Inc.

nanoFET-based devices have demonstrated capabilities that

may allow for accurate, fast, and multiplexed intracellular
recording.17,19,550
4.4.2. Intracellular-like Recording with Protruding
Metal Electrodes. The existence of an extracellular cleft
between the living cell membranes and the planar substrate
used to support recording devices can reduce electrical coupling
and corresponding signal levels. As discussed above in section
4.1.4, a number of approaches have focused on decreasing the
cleft size and consequently increasing the seal resistance as a
means to enhance signals. Spira and co-workers significantly
increased the seal resistance by functionalizing micrometer-
sized, mushroom-shaped gold protrusions, thereby forming
tight coupling with the cell membrane.536,551−553 This approach
was further confirmed by Offenhäusser and co-workers.554
Systematic investigations of the cleft width between the plasma
membrane and protruding gold electrode surfaces reveal that
these structures significantly enhance the contact, in particular Figure 21. Intracellular-like recordings with FGSEs. (a) Experimental
at the protruding head region. As an example, studies of an setup with one cell interfaced to a single glass microelectrode (red)
Aplysia neuron cultured on a chemically functionalized gold- and FGSE (blue). (b) Calibrated recording from the intracellular
spine electrode (FGSE) and simultaneously interrogated with a microelectrode (red) and FGSE (blue) for a pulse of 5 mV, 20 ms. (c)
patch-clamp microelectrode (Figure 21) showed several key A hyperpolarizing current pulse (purple) induced hyperpolarization
points. First, injection of a hyperpolarizing current with the recorded by the intracellular microelectrode (red) and the FGSE
(blue). (d−f) Depolarizing currents generated action potentials with
patch-clamp electrode yielded 10 and 5 mV recorded
amplitudes of ∼50 mV (intracellular microelectrode, red) and ∼25 mV
polarizations using the patch clamp and FGSE (Figure 21c). (FGSE, blue). Reprinted with permission from ref 553. Copyright
In addition, injection of depolarizing currents led to the 2010 Nature Publishing Group.
observation of intracellular action potentials that were
temporally correlated between the patch clamp and FGSE 4.4.3. Intracellular 3D Nanowire Transistors. The
(Figure 21d−f), although the amplitudes were approximately 2- nanoscale dimensions of SiNW FETs make them potentially
fold smaller for the FGSE (25 mV) versus the patch clamp (50 ideal as intracellular probes because (i) their small size should
mV). These observations demonstrate that functionalized allow for minimally invasive insertion and (ii) the FET device
FGSEs can record intracellular-like responses from electrogenic holds the promise for true intracellular recording, since it is
cells and thus provide significant information beyond that nearly independent of interfacial impedance in contrast to
obtained from conventional planar metallic microelectrodes passive electrode techniques. Nevertheless, the overall size of all
and MEAs. conventional nanoFETs, which have a linear device geometry,
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is much larger than the active FET component due to the 22b). Initially, only an extracellular action potential was
source and drain electrical contacts. The necessity of having observed, and then after ca. 40 s, the extracellular signal
two contacts makes minimally invasive insertion of a nanoFET gradually disappeared with concomitant increase in a new signal
into cells difficult if not impossible. consistent with the intracellular action potential. Finally, at
A breakthrough that first overcame this geometry-size steady state an intracellular action potential with an average
constraint was achieved with synthesis on nonlinear kinked peak amplitude of ∼80 mV and duration of ∼200 ms was
NWs.73 The kinked structure allows for localization of a recorded, which is consistent with true intracellular recording.
pointlike FET detector at the kinked NW tip, with metal Following this pioneering work, 3D FET-based NW−
contacts geometrically removed from this probe tip (Figure nanotube and kinked p−n junction nano-bioprobes were also
22a), thereby allowing for the realization of bioprobes capable investigated for intracellular recordings.120,555−559 For example,
recording using branched nanotube−NWs was reported in
2012.556 In this work, a branched SiO2 nanotube was
synthetically integrated on a SiNW transistor (Figure 22c),
modified with a phospholipid bilayer, which allowed
penetration through cardiomyocyte cell membranes, followed
by intracellular action potential recording by the SiNW FET.
The intracellular potential functions as an electrolyte gate
through the nanotube, thereby modulating the conductance of
the nanoFET. Significantly, by using multiple branched SiNW
FETs, the authors demonstrated multiplexed intracellular
electrical recordings from both single cells and cell networks.
A limitation of these chip-based 3D nano-bioprobes has been
the difficulty in exploiting the nanometer-scale probe resolution
in a deterministic manner to record from specific cell regions
and/or subcellular structures. To overcome this limitation,
Qing et al. fabricated free-standing probes with a kinked-SiNW
nanoFET sensor.558 Under a standard microscope, these probes
were manipulated in 3D space to target specific regions and
obtain stable, full-amplitude intracellular action potential spikes.
Compared to the signal measured from patch-clamp probes on
the same cell, the free-standing NW probe showed the same
amplitude and temporal properties (Figure 22d), thus
demonstrating the capability to record true intracellular (vs
intracellular-like) properties.
The substantial progress in intracellular recording described
above was made possible by the availability of nanostructures
with similar characteristic length scales to natural biological
functional substructures. Semiconductor NW building blocks
excel among nanomaterials in their capabilities to be rationally
designed and synthesized with complex motifs with near
molecular-scale precision. It is worth noting that applications of
semiconductor NWs in biology are still at an early stage with
Figure 22. Intracellular recordings with SiNW FETs. (a) Schematics
future research needed to better understand and ultimately
of cellular recording from a cardiomyocyte monolayer on a PDMS exploit the biochemical mechanisms that yield nanoFET−cell
support (left) and extracellular (middle) and intracellular (right) interfaces.
NW−cell interfaces. The inset is an SEM image of the kinked- 4.4.4. Intracellular MEA-Based Nanopillars. Substantial
nanowire device. Purple lines denote the cell membrane and NW lipid effort has been placed on the development of vertical NW
coating. (b) Plots corresponding to (i) extracellular, (ii) extracellular electrode arrays. In 2012, Park and co-workers demonstrated
to intracellular transition, and (iii) steady-state intracellular recording. parallel electrical interfacing to mammalian neurons using
Reprinted with permission from ref 54. Copyright 2010 American vertical NW electrode arrays (Figure 23a−c).560 The NWs in
Association for the Advancement of Science. (c) A branched SiO2 the arrays were 150 nm in diameter and 3 μm in height with
nanotube integrated on top of a SiNW transistor. Reprinted with
Ti/Au metallic tips, where each addressable electrode consisted
permission from ref 556. Copyright 2012 Nature Publishing Group.
(d) Optical image of a kinked-NW probe (left) and patch-clamp of nine NWs. To achieve recording it was necessary to apply
pipette (right) recording from the same cell. Reprinted with voltage/current pulses, which can electroporate the cell
permission from ref 558. Copyright 2014 Nature Publishing Group. membrane, although the spike amplitudes were much smaller
than the true intracellular signals (Figure 23d). In parallel, Cui
and co-workers reported using vertical Pt NWs electrodes (150
of facile intracellular recordings.54 An interesting feature of nm in diameter and 1−2 μm in height) to record extracellular
these nanoFET probes was modification with phospholipid and intracellular action potentials from cultured cardiomyo-
bilayers to promote spontaneous cellular internalization cytes, although the peak amplitudes were less than the full-
without external forces. Indeed, contact of cultured cardiomyo- amplitude intracellular action potential.561 This work also used
cyte cells to a 3D kinked SiNW bioprobe showed three electroporation to assist short-term penetration of the NWs
distinguishable recording stages during internalization (Figure across the cell membrane. In these two vertical metallic NW
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coupling. Moreover, given the intrinsic 3D interconnectivity of

cells in tissues, consideration of the mechanical properties and
connectivity of the nanoelectronic devices will also be critical.
These latter factors are typically not considered in recording
single cells for 2D in vitro cell cultures. Previously, several
different types of micro- and nanostructure-based electrodes
have been used as tools for interfacing to tissues,567−570
although they are outside the scope of this review. Below we
will introduce cutting-edge studies that have exploited SiNW
and graphene transistors for interfacing to brain and heart
tissues, and additionally, will review how their integration into
flexible electronics can open up new opportunities in
bioelectronics.
5.1. Acute Brain Slice Studies with Nanowire Transistors
In 2010, Qing et al. reported studies in which SiNW FET arrays
fabricated on transparent substrates were interfaced to acute
brain slices to yield submillisecond temporal resolution and
Figure 23. (a) SEM image of a vertical NW electrode array. (b) better than 10 μm spatial resolution.173 The transparent device
Stimulation/recording pads for multisite interrogation of neuronal
chip allowed for imaging of individual cell bodies and
circuits. (c) A rat cortical cell on the NW array. (d) Action potentials
stimulated using a patch pipette (blue) and recorded by the NW array identifying areas of healthy neurons on both upper and lower
(magenta). Reprinted with permission from ref 560. Copyright 2012 tissue surfaces. The small active device area (0.06 μm2) and
Nature Publishing Group. array spacing (3 μm) enable highly localized multiplexed
measurements of neuronal activities and, for example, provided
studies, the intracellular-like access gained by electroporation information addressing signal propagation in the lateral
was transient, in contrast to the long-term access of lipid-coated olfactory tract and functional neural connectivity in the
SiNW FETs reported by the Lieber group. Notably, Melosh olfactory cortex. Figure 24a shows a NW FET array under an
and co-workers have also shown that proper surface acute brain slice that was stimulated at different locations. On
functionalization can help electrodes similar to those used in the basis of the time and distance difference for stimulation, it
the Park and Cui studies to gain intracellular access.562−565 was possible to estimate a propagation rate as 1.6−2 m/s in the
More recently, Cui and co-workers have reported MEA- lateral olfactory tract. To demonstrate the capability to probe
the activity patterns, eight devices within a four-by-four array
based nanoelectrodes consisting of iridium oxide (IrO2)
were simultaneously monitored while eight different locations
nanotubes.566 When these IrO2 nanotube-based chips were
were stimulated in the lateral olfactory tract (Figure 24b).
used as a substrate for cardiomyocytes culture, the cell
Similar responses are obtained by each device irrespective of
membrane wrapped around the vertical nanotubes and
the stimulation positions after a strong stimulation that can
protruded into the hollow spacing between adjacent nanotubes,
thus suggesting that the nanotube array geometry could be activate all axons fibers, as revealed in Figure 24c. Reducing the
beneficial for creating tight cell−electrode junctions similar to stimulation intensity, such that only a limited number of axon
those achieved with FGSEs. Consistent with this structural are activated, yielded data (Figure 24d) that unambiguously
observation, the authors observed larger and more stable revealed device-specific features. In this weak stimulation
intracellular action potentials from the beating cardiomyocytes, regime, 2D activity maps from all eight devices (Figure 24e)
with amplitudes closer to the expected full amplitude measured demonstrated clearly heterogeneous activity and unique
with patch-clamp pipettes. pairwise activity correlations for different stimulation spots.
The above results show that vertical NWs can bridge For example, the signals from devices 1 and 8 showed close
microelectrode−cell interfaces and allow direct access to correlation for 5/8 stimulation spots, while those from devices
intracellular information like FGSEs. However, the current 3 and 4 show close correlation for only 3/8 stimulation spots.
vertical NW MEAs have several limitations, including (i) high These studies provided the first example of how highly localized
electrochemical impedance due to the small contact area, which direct electrical recording from intact neural networks using
has generally been overcome by using multiple NWs as a single nanoelectronic devices could serve as a powerful approach to
electrode, and (ii) recorded intracellular potentials that are visualize the dynamic, functional neural networks and thus
about 10 times lower than the patch-clamp signals. Future provide key information necessary to understand circuits and
research on the effects of NW surface modification should be plasticity.
investigated to improve the internalization of these NW-based 5.2. Cardiac Tissue Studies with Nanowire Transistors
MEA electrodes as well as cell sealing, which could improve the Spontaneously beating embryonic chicken hearts were also
stability and signal-to-noise ratio of the observed signals. studied using bottom-up SiNW FETs on planar substrates
(Figure 25a,b).571 The fabrication process yields protruding
5. NANOELECTRONICS−TISSUE INTERFACES AND NW FET channels from the underlying chip and thus could
ELECTROPHYSIOLOGICAL RECORDING enhance coupling to heart tissue. Simultaneous recordings from
Making effective electrode−tissue interfaces requires consid- a beating heart using a NW FET and a conventional glass
eration of the interfacial contact between electrodes and the 3D pipette (Figure 25c) showed close temporal correlation, except
cell networks comprising functional tissues. In this regard, the for a ∼100 ms delay in the NW FET peak consistent with the
position, shape, and size of an electrode with respect to the separation of electrodes. Individual signals recorded from FET
target tissue are all critical factors determining this contact or devices exhibited two characteristic components, that is, initially
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Figure 25. (a) Image of experimental setup for NW FET−heart

interface and recording. Arrows denote the positions of heart (red),
Ag/AgCl reference electrode (yellow), and source/drain interconnect
wires (blue), respectively. (b) Top: Magnified image of heart on the
device. Bottom: Zoomed-in view of the dotted region in upper image,
showing three pairs of NWs with the orientation along the vertical red
lines. (c) Parallel recordings made using a glass pipette (black) and
Figure 24. (a) Top: Optical image of an acute brain slice covering a NW FET (red). (d) Peak conductance amplitude (red) and calibrated
linear array of NW FETs with the array perpendicular to the lateral peak voltage amplitude (blue) as a function of gate voltage. (e) Image
olfactory tract fiber. Red circles denote three devices for recording of a complete chip on a flexible Kapton substrate, where the central
while the x’s denote the positions of two stimulation electrodes, dashed box denotes the position of NW FETs. (f) Measured signals at
corresponding to distances ca. 400 μm (red) and 1200 μm (green) a gate of −0.2 V. Reprinted with permission from ref 571. Copyright
from the NW array. The inset is a schematic of the experimental 2009 American Chemical Society.
configuration. Bottom: Conductance versus time traces from devices
1−3 following stimulation at red and green crosses, respectively; the (Figure 25d). The relatively constant recorded junction voltage
curves correspond to averages of eight recordings. (b) Optical image
of an acute slice covering a 4 × 4 NW FET array. Numbers 1−8
confirmed the robust nanoFET−heart interface.
denote the device positions while the crosses denote the eight Last, the authors also fabricated NW FET devices on a
stimulation spots. (c) Averaged signals from 15 recordings following flexible polymer substrate (Figure 25e) which enabled
stimulation (200 μs/400 μA pulses). The inset is the normalized map simultaneous recording from an isolated beating heart from
of the signal intensity from the eight devices deduced from the shaded multiple devices (Figure 25f). Notably, the calibrated voltages
area in each trace. (d) Representative recordings (averaged from 12) associated with the fast transient for three NW FET devices, 5.3
from devices 1 and 8 for stimulations at spots a−h (200 μs/100 μA ± 0.2, 4.6 ± 0.1, and 5.3 ± 0.2 mV, further highlight the
pulses). (e) Maps of the relative signal intensity for devices 1−8. reproducibility of the nanoFET−heart interfaces. Moreover, the
Reprinted with permission from ref 173. Copyright 2010 National significantly larger signal-to-noise ratio for the fast transient
Academy of Sciences of the United States of America. implies a tighter interface contact due to the flexible substrate.
5.3. Cardiac Tissue Studies with Graphene Transistors
fast and subsequently slower ones. Further measurement made More recently, graphene FETs have also been used to record
with and without blebbistatin, which prevents contraction while newborn rat hearts.546 Graphene FET devices with channel
maintaining ion channels excitability, demonstrated that the fast widths ranging from 10 μm to 200 nm were interfaced to the
component was associated with ion-channel current. Studies of spontaneously beating hearts, and the local field potential was
the fast transient peak made as a function of water-gate recorded as a current change in the FET (Figure 26a).
potential showed a conductance change from ca. 55 to 11 nS, Interestingly, measured signals recorded from both planar and
while the voltage-calibrated signals were constant, 5.1 ± 0.4 mV suspended graphene devices (Figure 26b) show regularly
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Figure 26. (a) Circuit schematic for the graphene−cell interface. (b) Signals from a beating heart recorded by a graphene FET before (black) and
after the device was suspended (red). Right panels correspond to zoomed-in views denoted by the stars in the left panels. Reprinted with permission
from ref 546. Copyright 2013 American Chemical Society.

Figure 27. Nanoelectronic scaffolds (nanoES) and synthetic tissues. (a, b) Confocal fluorescence microscopy and SEM images, respectively, of two
nanoES. (c) Confocal fluorescence micrographs of a hybrid nanoES/cardiac synthetic tissue patch. (d) Epifluorescence micrograph of the surface
from the same hybrid with the position of NW FET source−drain electrodes highlighted by the white dashed lines. (e) Time evolution of periodic
conductance spikes recorded by a NW FET device in the nanoES/cardiac hybrid before and after addition of noradrenaline. (f) Multiplex recordings
from four NW FETs in a nanoES/cardiac hybrid. Reprinted with permission from ref 21. Copyright 2012 Nature Publishing Group.

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spaced spikes with a fast biphasic peak that lasts for 3D interconnected and addressable macroporous nanoelec-
milliseconds, consistent with extracellular recording from fast tronic networks.22 Hundreds of addressable NW devices, with
sodium ion channels that open at the start of each AP/ feature sizes from 10 nm scale (for device elements) to 10 μm
heartbeat. In addition, the suspended devices yield an increased scale (for electrical and structural interconnections), were
(>3-fold) signal amplitude and decreased (∼2-fold) noise, thus incorporated in these 3D networks (Figure 28). Significantly,
allowing the much weaker ionic currents of calcium ion
channels to be resolved.
5.4. 3D Nano-Bioelectronic Hybrids
An important goal in tissue engineering is to construct culture
systems as close as possible to the biological, physical, and
chemical environment of the natural extracellular matrix
(ECM).572 2D bioelectronics have been used in studies of
engineered tissues,573 although the recording devices are not
capable of mapping the critical 3D behavior of the tissue as a
whole. Overcoming this basic limitation requires the develop-
ment of nanoelectronic recording devices in a 3D architecture,
which necessitates the following features: (i) macroporous
structures to allow for cell interpenetration during culture, (ii)
nanometer to micrometer scale structural features consistent
with the ECM or tissue scaffolds, and (iii) mechanical
properties similar to the ECM for tissue development.7,19
Tian et al. demonstrated the first example of using
macroporous NW nanoelectronic scaffolds (nanoES) to
develop innervated synthetic tissues.21 In this new paradigm,
SiNW transistors were fabricated into network structures,
where the network, which contains electrical interconnects
needed to address the nanoFETs, was designed to have feature
sizes and porosities similar to those of a conventional passive
tissue scaffold. Second, the nanoES was released from the
underlying substrate and configured as a 3D macroporous
scaffold by either stress-induced self-organization or external
forces. The porosity of nanoES can exceed 99%, which renders
the scaffold to high flexibility (Figure 27a,b). Last, the nanoES
was combined with biodegradable ECMs and seeded with cells,
and then the assembly was cultured to produce synthetic tissues Figure 28. (a) Schematic of 3D macroporous NW structure
innervated in 3D with nanoFETs. highlighting the simultaneous confocal fluorescence and photocurrent
The structure of a representative nanoES/cardiac hybrid imaging to localize the positions of NW FET devices: blue cylinder,
characterized by confocal fluorescence microscopy and NW; orange-red, polymer mesh network; green dot, laser spot. (b) 3D
reconstructed confocal fluorescence/photocurrent microscopy image
epifluorescence microscopy (Figure 27c,d) highlights the high
of a 3D mesh structure. The polymer mesh structure is red-orange and
density of cardiomyocytes in close contact with nanoES NW FET positions are green. (c) 3D micro-CT image of a strain
components. Clear striations of cardiac tissue, indicative of sensor array embedded in an elastomer, where metal interconnects are
mature tissue, were also observed. The monitoring capability of visible as yellow-orange lines. (d) Optical image of a typical NW
the 3D nanoES/cariac hybrid was demonstrated by recording device. The white arrow points to the NW, and source (S) and drain
from a single-NW FET located below the construct surface as (D) are highlighted with blue and pink coloring, respectively. (e) 3D
shown in Figure 27e. The data revealed regularly spaced spikes strain field mapped by the NW strain sensors (left) and image of
with a frequency of ∼1 Hz, calibrated potential change of ∼2−3 elastomer with embedded macroporous NW network (right).
mV, signal-to-noise ratio of ≥3, and ∼2 ms width, all of which Reprinted with permission from ref 22. Copyright 2013 National
agree well with expectations for extracellular recordings from Academy of Sciences of the United States of America.
cardiomyocytes. Moreover, addition of norepinephrine, a drug
that stimulates cardiac contraction, showed a 2-fold increase of simultaneous NW photocurrent and confocal microscopy
the contraction frequency. Given the capability to resolve imaging studies demonstrated that it was possible to localize
action potentials with single-shot submillisecond time reso- NW positions inside 3D hybrid materials with ∼14 nm
lution in 3D (Figure 27f), this work suggests substantial resolution. This method should prove particularly useful in the
potential for the nanoES/cardiac hybrids and other tissue future for mapping the positions of the nanodevices to high-
hybrids as a new paradigm for 3D monitoring and screening of resolution with respect to cells. The success of integrating 3D
drugs. multifunctional nanoelectronics with biological hosts indicates
Further development of the nanoES paradigm has been the capability of fabricating truly 3D nanoelectronic circuits and
achieved in the seamless incorporation of active nanoelectronic subsequent 3D incorporation of these multifunctional circuits
networks within 3D materials, where active monitoring and into living systems for smart materials and even “cyborg”
control of host systems have been exhibited by multifunctional tissues, although additional work will be needed before the
NW electronics. For example, Liu et al. reported the conversion nanoES-based hybrids can be used as implants in vivo. Last, it
of ordered 2D NW nanoelectronics precursors into ordered, should be noted that the basic nanoES paradigm is amenable to
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Chem. Rev. 2016, 116, 215−257
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Figure 29. (a) Schematics for injectable electronics. The needle is inserted (i) and retracted (ii) to leave the mesh electronics in the cavity. (b)
Schematic of the mesh design, where α is the angle with respect to a rectangular configuration. (c) Optical image of a longitudinal brain slice taken 5
weeks after injection into the hippocampus. The mesh is fully extended. (d) A 16-channel recording with the mesh electronics following injection
into the brain of a live mouse. Reprinted with permission from ref 23. Copyright 2015 Nature Publishing Group.

incorporation of additional types of functional devices, Notably, studies of the chronic tissue response following
including photonic devices as well as strain and biochemical injection of the macroporous mesh into live rodent brains
sensors, and these could further broaden the capabilities and (Figure 29c) demonstrated several new and exciting features,
opportunities for in vitro and in vivo studies of the brain and including (i) filling in of neural tissue through the macroporous
heart in the future. network, (ii) minimal or absence of astrocyte proliferation in
5.5. Injectable Electronics
the vicinity of the injected probe, and, correspondingly, (iii)
attractive interactions between the neurons and the macro-
The mismatch of mechanical properties represents an essential porous mesh, which led to the formation of tight electronics/
challenge at the tissue−electrode interface. Tissues are soft and cell junctions that are ideal for recording. Indeed, the mesh
flexible, also with interior cell migration, while the implanted electronics have proved to be able to record well-defined neural
electronics made, for example, of metal or silicon, have rigid activity from live mice brains (Figure 29d). In this case, the
nonporous structures. This difference results in two disadvan- rigid shell of the syringe allowed placement of the mesh in
tages. First, rigidity can yield incomplete and/or ineffective specific brain regions. In parallel, they also developed another
contacts, which lead to weak signals that may be overwhelmed method to implant the ultraflexible 3D macroporous electronic
by noise.574−576 Second and perhaps more important, these device into rodent brains by rapid freezing in liquid nitrogen
rigid probes are known to illicit a chronic immune response and inserting the probe in the frozen state.24 Significantly, the
that results in the buildup of glial scar tissue around the probe, chronic histology studies, which revealed filling in of neural
where the biologically inactive scar tissue can diminish or tissue through the macroporous network and attractive neuron
eliminate recorded and/or stimulation signals.577,578 Over- probe interactions, contrast results from other solid and more
coming these long-standing limitations of existing implantable rigid probe designs and are consistent with a unique long-term
electrode probes requires greater attention to the importance of stability and biocompatibility of the ultraflexible mesh probe−
the electrode−tissue interfaces and matching of overall probe/ tissue interface. Although it will be important in future studies
tissue mechanical properties. to develop these probes further, for example by extending the
Significantly, the Lieber group recently proposed and chronic histology studies to shorter and longer times and
demonstrated a new paradigm that overcomes these long- increasing the number of sensor elements available for
standing challenges through syringe injection of centimeter- multiplexed recording and/or introducing stimulation capa-
scale macroporous electronic networks.24,174 In this new bilities, the new paradigm of syringe-injectable macroporous
approach (Figure 29a), the syringe is loaded with the mesh electronics promises to be transformative in capabilities
ultraflexible mesh and inserted into the tissue or cavity, and for stable chronic brain activity mapping through the
development of implants for next-generation brain−machine
then the mesh is injected while simultaneously retracting the
interfaces.
needle. The mesh structure is critical for controlling the
bending stiffness and allowing loading/injection. Specifically,
the angle α (Figure 29b) determines the bending stiffness of 6. CONCLUSIONS
the unit cell. The authors found that when α = 45°, the mesh In this review, two general classes of nano-bioelectronic sensor
electronics can be smoothly delivered through a needle with an devices were discussed. First, we introduced nanoFET sensors
inner diameter that was >30 times smaller than the original for label-free, real-time detection of chemical and biomolecular
mesh width (W). species. The synthesis of the crucial building blocks for these
242 DOI: 10.1021/[Link].5b00608
Chem. Rev. 2016, 116, 215−257
Chemical Reviews Review

sensors, including SiNWs, SWNTs, and graphene, was planar substrates has made it difficult to demonstrate these
overviewed in addition to discussing basic characteristics of unique resolution capabilities in a compelling biological
FET devices and nanoFET sensors configured from these problem. We believe that the more recent efforts incorporating
nanomaterials. Representative sensing studies of key biomo- nanoelectronics into three-dimensional synthetic or in vivo
lecular targets were then reviewed, including detection of
tissues offers perhaps the greatest opportunities for revolu-
proteins, nucleic acids, viruses, and small molecules. These
studies have demonstrated clearly the success of the nanoFET tionary advances.21−24 In this direction, one can envision
biosensor concept388 across nanomaterial building blocks, building many nanoelectronic devices into cellular circuitry and
where sensing targets were diversified through surface merging this circuitry in a seamless manner with biological
functionalization with conjugate probe molecules/receptors. information processing systems, such as the brain. Extending
This latter functionalization point was further highlighted such concepts to rational design and fabrication of multifunc-
through review of multiplexed electrical detection studies, tional nano-bioelectronic device networks and circuits could
where multiple nanoFET devices in the same array were
further inspire and lead to a new understanding of the interplay
modified with different probe molecules to allow for
simultaneous electrical recording of different disease marker between nanostructures and biosystems. In particular, we
proteins and viruses. In addition, we discussed investigations suggest strongly that the frontier of the nanoelectronics−brain
focused on addressing and improving the ultimate sensitivity of interface focused on in vivo brain activity mapping and
nanoFET biosensors, including (i) the use of 3D branched modulation with high spatial and temporal resolution
NWs, (ii) detection in the FET subthreshold regime, (iii) represents a truly unique opportunity to impact fundamental
reduction of the effect of Debye screening, (iv) the use of research and ultimately healthcare with a substantial benefit to
electrokinetic effects to enhance local target concentration, and
society worldwide. More generally, as we take advantage of the
(v) measurements in the frequency domain. The sum of these
diverse and important studies has now defined a relatively uniquely small sizes of nanoelectronic devices organized into
comprehensive understanding of the original nanoFET arrays and circuits that have similar connectivity, feature sizes,
concept388 for chemical/biological detection. In addition, in and mechanical properties as the cell networks comprising
section 3.4 we discussed several basic challenges as well as living tissues of interest (e.g., the brain), we begin to blur the
potential research directions that could improve further the distinction between the nonliving electronic and living
capabilities of nanoFET biosensors. Beyond these suggested biological systems, and we suggest that this will lead to major
directions and given the increasingly well-defined characteristics and sometimes unexpected opportunities in understanding
of nanodevice−receptor interfaces, we believe it would also be
timely to consider modeling and simulation studies, since these complex biological systems and diseases and potential new
could provide both deeper understanding and the feedback therapeutic directions.
required for further improvements in, for example, the
sensitivity in physiological environments. AUTHOR INFORMATION
In addition, we believe there are important opportunities to Corresponding Author
impact both applications and fundamental research in the life
sciences and healthcare with nanoFET biosensors. For example, *E-mail: cml@[Link].
the existing state of nanoFET technology is now suitable as a Notes
general multiplexed detection platform when either external or
on-chip sample preparation is employed to lower ionic strength The authors declare no competing financial interest.
of physiological samples. Developing large nanoFET sensor Biographies
arrays could also move beyond current technologies and take
advantage of information emerging from genomics and
proteomics to improve the diagnosis and treatment of cancer
and other complex diseases, where real-time data acquisition
possible with the nanoFETs would serve as a unique capability
compared to optical methodologies. Moreover, we suggest that
further development of methods that enable direct nanoFET
detection in physiological fluids will be especially impactful in
near-term development of in vitro clinical/healthcare diag-
nostics, as well as opening up unique opportunities associated
with real-time detection of proteins/protein expression, nucleic
acids, and small molecule “drugs” using nanoFETs directly
implanted into cells and tissues.
The second part of the review focused on studies extending
the use of nano-bioelectronic devices to extracellular and
intracellular electrophysiological recording/stimulation from Anqi Zhang received her bachelor’s degree in materials chemistry from
live cells, including neurons and cardiomyocytes. The results Fudan University in China in 2014. She is currently a Ph.D. student
obtained using emerging nano-bioelectronic tools have
under the supervision of Prof. Charles M. Lieber in the Department of
demonstrated the capability to obtain higher spatial and
temporal resolution data than possible using more established Chemistry and Chemical Biology at Harvard University. Her research
MEA and patch-clamp technologies. Nevertheless, the fact that interests include development of novel nano-bioelectronic tools and
many of the nanoelectronic devices have been constrained to their applications in neurophysiology.

243 DOI: 10.1021/[Link].5b00608

Chem. Rev. 2016, 116, 215−257
Chemical Reviews Review

(10) Dasgupta, N. P.; Sun, J.; Liu, C.; Brittman, S.; Andrews, S. C.;
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Charles M. Lieber is the Mark Hyman Professor of Chemistry and based nanoelectronic devices in the life sciences. MRS Bull. 2007, 32,
Chair of the Department of Chemistry and Chemical Biology at 142−149.
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Harvard University. He received his Ph.D. from Stanford University
Transistor-Based Biosensors for Biomedical Diagnosis and Cellular
(1985) and completed postdoctoral studies at the California Institute
Recording Investigation. Nano Today 2011, 6, 131−154.
of Technology (1987). His research is focused on the chemistry and (17) Tian, B.; Lieber, C. M. Design, synthesis, and characterization of
physics of nanoscale materials with a current emphasis on synthesis of novel nanowire structures for photovoltaics and intracellular probes.
novel nanowire structures and the development of novel nano- Pure Appl. Chem. 2011, 83, 2153−2169.
electronic platforms for probing and interfacing with biological (18) Yang, L.; Li, Y.; Fang, Y. Nanodevices for Cellular Interfaces and
systems. His work has been recognized by numerous awards, including Electrophysiological Recording. Adv. Mater. 2013, 25, 3881−3887.
the Wolf Prize in Chemistry (2012), the Gibbs Medal (2013), and the (19) Tian, B.; Lieber, C. M. Synthetic nanoelectronic probes for
IEEE Nanotechnology Pioneer Award, and his published papers have biological cells and tissues. Annu. Rev. Anal. Chem. 2013, 6, 31−51.
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ACKNOWLEDGMENTS Langer, R.; Kohane, D. S.; Lieber, C. M. Macroporous nanowire
We thank Ying Fang (National Center for Nanoscience and nanoelectronic scaffolds for synthetic tissues. Nat. Mater. 2012, 11,
Technology) for helpful discussion and Teng Gao (Harvard 986−994.
University) for help with preparing the table of contents (22) Liu, J.; Xie, C.; Dai, X.; Jin, L.; Zhou, W.; Lieber, C. M.
Multifunctional three-dimensional macroporous nanoelectronic net-
graphic. C.M.L. thanks the Air Force Office of Scientific
works for smart materials. Proc. Natl. Acad. Sci. U. S. A. 2013, 110,
Research, Fidelity Biosciences Fund, McKnight Foundation
6694−6699.
Technological Innovations in Neurosciences Award, NIH (23) Liu, J.; Fu, T.-M.; Cheng, Z.; Hong, G.; Zhou, T.; Jin, L.;
Director’s Pioneer Award, National Security Science and Duvvuri, M.; Jiang, Z.; Kruskal, P.; Xie, C.; et al. Syringe-injectable
Engineering Faculty Fellow Award, and Star Family Fund for electronics. Nat. Nanotechnol. 2015, 10, 629−636.
generous support of the studies from the authors’ laboratory (24) Xie, C.; Liu, J.; Fu, T.-M.; Dai, X.; Zhou, W.; Lieber, C. M.
that contributed to this review. Three-dimensional macroporous nanoelectronic networks as mini-
mally invasive brain probes. Nat. Mater. 2015, 14, 1286−1292.
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257 DOI: 10.1021/[Link].5b00608

Chem. Rev. 2016, 116, 215−257