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PERSPECTIVE

The Smartest Materials: The Future of


Nanoelectronics in Medicine
Tzahi Cohen-Karni,†,§ Robert Langer,‡,§ and Daniel S. Kohane†,*

Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Division of Critical Care Medicine, Children's Hospital Boston, Harvard Medical School,
300 Longwood Avenue, Boston, Massachusetts 02115, United States, and ‡Department of Chemical Engineering and §David H. Koch Institute for Integrative Cancer
Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States

O
ver the past several decades, elec-
tronics have become central to ABSTRACT
many aspects of biomedicine, rang-
ing from fundamental biophysical studies
of function in excitable tissues, such as the
heart and brain, to medical monitoring
and interventions. Implantable pacemakers
and defibrillator devices have allowed Electronics have become central to many aspects of biomedicine, ranging from fundamental
the detection and treatment of cardiac
biophysical studies of excitable tissues to medical monitoring and electronic implants to
arrhythmias,1 and “grids-and-strips” devices
have been used to map cerebral cortical restore limb movement. The development of new materials and approaches is needed to
activity in epilepsy.2 Deep brain stimulation enable enhanced tissue integration, interrogation, and stimulation and other functionalities.
(DBS) has been delivered by implanted Nanoscale materials offer many avenues for progress in this respect. New classes of molecular-
electrodes for the treatment of the disabling scale bioelectronic interfaces can be constructed using either one-dimensional nanostructures,
motor symptoms of Parkinson's disease, such as nanowires and nanotubes, or two-dimensional nanostructures, such as graphene.
essential tremor, and dystonia.3 Recently,
Nanodevices can create ultrasensitive sensors and can be designed with spatial resolution as
there has been a growing interest in the
development of electrical interfaces with fine as the subcellular regime. Structures on the nanoscale can enable the development of
tissues, and in electronic implants to restore engineered tissues within which sensing elements are integrated as closely as the nervous
limb movement directly or via a brain- system within native tissues. In addition, the close integration of nanomaterials with cells and
to-machine interface to control a robotic tissues will also allow the development of in vitro platforms for basic research or diagnostics.
arm.4,5 An artificial retina has been devel- Such lab-on-a-chip systems could, for example, enable testing of the effects of candidate
oped that combines state-of-the-art micro-
therapeutic molecules on intercellular, single-cell, and even intracellular physiology. Finally,
fabrication techniques to create photo-
voltaic elements that will supply the energy advances in nanoelectronics can lead to extremely sophisticated smart materials with
needed for stimulation of subretinal neu- multifunctional capabilities, enabling the spectrum of biomedical possibilities from diagnostic
rons in order to transfer an image to the studies to the creation of cyborgs.
visual cortex.6 Such a fully integrated wire-
less implant is a step toward the restoration
of vision to patients blinded by degenera-
tive retinal diseases.
Nanomaterials and Nanoelectronics. The pre-
one-dimensional wires and tubes,8 two-
ceding examples show the enormous po-
dimensional layered materials,9 and three-
tential of implanted electronics in the
dimensional assemblies of the lower-order
human body. As in many other fields of building blocks.10 The wide range of purposes
science, the furtherance of such technolog- for such devices includes delivery of molecu-
ical advances will necessitate the develop- les of interest,11 tissue engineering,12,13 and
ment of new materials and approaches, to nanogenerators for self-sustained biosystems.14
enable enhanced tissue integration, inter- One-dimensional nanostructures such as * Address correspondence to
rogation, and stimulation of tissues and nanowires and nanotubes15,16 serve as pro- daniel.kohane@childrens.harvard.edu.
other functionalities. Nanoscience offers many mising nanoelectronic building blocks for a
avenues for progress in this respect. Recent variety of applications including sensing,17,18
Published online July 31, 2012
years have seen the development of a photonics,19 energy conversion,14,20 and elec- 10.1021/nn302915s
wide range of nanoscale materials (Figure 1), trical devices capable of forming complex
including zero-dimensional nanoparticles,7 logical functions.21 A variety of materials can C 2012 American Chemical Society

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PERSPECTIVE
Figure 1. Nanomaterials in biomedicine. (A) Zero-dimensional (0D) nanoparticles for triggered release of drugs. Transmission
electron micrograph (TEM) of superparamagnetic iron oxide nanoparticles. Inset: Diffraction pattern suggests an ensemble of
randomly oriented crystalline particles. (B) Proposed schematic of a cross section of a nanocomposite membrane, showing
nanogel particles (blue), iron oxide nanoparticles (dark brown), and an ethylcellulose matrix (light brown). Upon application
of an oscillating magnetic field, the ferromagnetic iron oxide nanoparticles release heat (orange) and reversibly shrink the
nanogels, enabling release of a drug (green) from a reservoir contained by the membrane. Adapted from ref 11. Copyright
2011 American Chemical Society. (C) One-dimensional (1D) nanowires in tissue engineering. (I) TEM of a typical distribution of
gold nanowires, with an average length of ∼1 μm and average diameter of 30 nm. (II,III) SEM revealed that the nanowires
(1 mg mL 1) assembled within the pore walls of the scaffold into star-shaped structures with a total length scale of 5 μm. The
assembled wires were distributed homogeneously within the matrix (II) at a distance of ∼5 μm from one another (III). Adapted
with permission from ref 12. Copyright 2011 Nature Publishing Group. (D) Three-dimensional (3D) self-assembled nano-
structures. (I) Peptide amphiphile monomer composed of three segmental domains: a sequence bearing a biological signal, a
domain containing amino acids with a strong tendency to form β-sheets, and a hydrophobic alkyl tail. (II) Simulated structure
that will form is a cylindrical aggregate in which twisted β-sheets (red) collapse through hydrophobic interactions among
alkyl chains, thus displaying high densities of the biological signal. The blue regions represent water domains present in the
interior of the supramolecular structure. Adapted with permission from ref 13. Copyright 2012 American Association for the
Advancement of Science.

be used to achieve the aforemen- because of their high surface-to- subcellular building blocks of bio-
tioned applications, including those volume ratios, exhibit high sensi- logical entities, such as proteins
from periodic table groups IV (Si Ge), tivities with signal-to-noise ratios within the cell membrane. For si-
III V (InAs InP), II VI (ZnO),14 16 that outperform planar structures.17,18 milar reasons, they can monitor
and carbon-based materials such Therefore, they can be used as ultra- biological events with subcellular
as carbon nanotubes,22 graphene,9 sensitive sensors for various ana- resolution.
and either conductive or coordina- lytes including single virus particle The spatial resolution of extant
tion polymers.23 Electrical signal detection,24 protein sensing in the cell electrical interfaces, as well the
recording with nanostructures, such femtomolar range,17,18 and DNA degree to which they are integrated
as Si nanowires, has several advan- sequencing using nanowire-based with the surrounding tissue, is lim-
tages compared to conventional de- sensors.25 Nanostructures can also ited by their size scale, which is
tection techniques with planar field- enhance cellular adhesion and usually in the range of hundreds of
effect transistors (FETs) and multi- activity,26 28 perhaps because their micrometers to millimeters. They
electrode arrays (MEAs). Nanodevices, dimensions are closer to those of the are typically a few cells in length,

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PERSPECTIVE
which hinders the spatial resolution contain nanodevices would either engineered tissues within which
of stimulation or monitoring of elec- be left with a permanent residue nanostructured sensing elements
trical activity that can be achieved. (with or without enduring function- are integrated as closely as the ner-
To address the need for even smal- ality) or that residue would have to vous system is within native tissue.
ler devices;and spatial resolution be designed so that it can degrade. Electronic nanostructures also have
as fine as the subcellular regime;a As with all medical devices, it will the potential to provide electrical sti-
new class of molecular-scale bioelec- be important to demonstrate that mulation to the tissues within which
tronic interfaces can be constructed fouling does not readily impede they are incorporated. That stimula-
using either one-dimensional nano- function within the intended life- tion need not be purely electrical;
structures, such as nanowires and span of the device. Mechanical pro- an electrical impulse can initiate a
nanotubes, or two-dimensional nano- perties of biomedical nanoelectron- secondary event, just as it does in
structures, such as graphene. Nano- ics will have to be commensurate the efferent limb of the nervous
wire-based devices have been used with those of the target tissues. system. Thus, for example, electrical
to record extracellular signals from Biointegration;the interconnec- stimulation could trigger the re-
cultured neurons,29 cardiomyo- tion between these nanodevices lease of bioactive molecules stored
cytes, 30,33 brain slices,31 and whole and the recipient tissue;will be in nanoliter (or larger) quantities.43
embryonic chicken hearts.32,33 Re- important, as well. If inadequate, it Sensing and stimulation could be
cent developments in the synthesis can be enhanced by surface mod- linked, creating closed-loop feed-
of nanowires have enabled a free- ification with biomolecules that en- back systems that would be analo-
standing nanowire-based three- hance biointegration.41 gous to reflex arcs in the autonomic
dimensional nanoprobe (Figure 2A I),34 The close integration of nano- nervous system. Interestingly, even
which allows the recording of the materials with cells and tissues if not integrated within circuitry,
intracellular electrical activity of car- will also allow the development of conductive nanomaterials can en-
diomyocytes (Figure 2A II). Various in vitro platforms for basic research hance the electrical performance of
device geometries and synthetic ap- or diagnostics.42 Such lab-on-a-chip excitable tissues, for example, by
proaches have been developed to in- systems could, for example, enable enhancing wave propagation be-
ternalize electrical devices within cells, testing of the effects of candidate tween isolated cell clusters within
using different device geometries and therapeutic molecules on intercel- engineered scaffolds.12 Nanode-
synthetic approaches, such as silicon- lular, single-cell, and even intracel- vices could further affect tissue de-
nanotube-based devices.35 37 Such lular electrical activity. Furthermore, velopment simply by virtue of their
nanostructures can be assembled by the assembly and fabrication of morphologies; nanotopography
on flexible plastic substrates, as pre- multiple devices per chip, it is pos- has been shown to have a pro-
sented in Figure 2B I, II,31,38 40 allow- sible to investigate the effects of found impact on a wide range of
ing them to conform to the shape of multiple analytes on cellular pro- cellular activities, including cell
organs and tissues and enabling elec- cesses at a spatiotemporal resolu- differentiation, proliferation, and
trical monitoring and mapping of tion not easily achievable by other gene expression. 27 Moreover,
whole organs.38 40 means. nanoelectronics, whether implanted
The development of nanomater- as free-standing devices or inte-
ials;including nanoelectronics; grated within an engineered tis-
closely associated with tissues will The small scale of sue, could be assembled in a way
have to address numerous issues that will introduce new function-
other than the development of in-
nanomaterials could alities to an engineered tissue or
tricate circuitry. Biocompatibility allow the development implantable devices. The nano-
(local and systemic toxicity) may structures could not only incorpo-
be particularly important because
of engineered tissues rate sensing and stimulating
many of the materials used in the within which capabilities but also potentially
fabrication of nanoelectronics (for introduce computational capabilities
conduction, insulation, and support)
nanostructured sensing and energy-generating elements
are neither closely related to com- elements are integrated (either photovoltaic or piezoelectric
monly used biomaterials nor known elements14,20); in this way, one could
to be biodegradable. There is a re-
as closely as the fabricate a truly independent system
lative paucity of knowledge (and nervous system is that senses and analyzes signals, in-
even fewer firm conclusions) about itiates interventions, and is self-
the biological side effects of many
within native tissue. sustained. Future developments in
such materials, even with relatively this direction could, for example, lead
commonly used ones, such as gold. The small scale of nanomaterials to a synthetic nanoelectronic auto-
Tissues or devices engineered to could enable the development of nomic nervous system.

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PERSPECTIVE
Figure 2. Bio nano electrical interfaces from a single cell to a whole organ. (A) Single cell interfaced with a flexible free-
standing three-dimensional (3D) silicon nanowire (SiNW) device. (I) SEM image of a 3D nanoprobe. The scale bar is 5 μm. (II)
Recorded intracellular action potentials using a flexible 3D nanoprobe. Adapted with permission from ref 34. Copyright 2010
American Association for the Advancement of Science. (B) Assembled SiNW devices on a flexible substrate. (I) Top-down
photograph of a flexible NW system, which enabled overall registration between heart and lithographically defined markers
on the substrate. In this case, a 50 μm flexible substrate with assembled nanowire devices was interfaced with a spon-
taneously beating embryonic heart and monitored its electrical activity. The dashed white rectangle at the center of the chip
highlights the location of a nanodevice array. (II) Recorded conductance data from a nanodevice in the configuration shown in
panel A. Adapted from ref 32. Copyright 2009 American Chemical Society.

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Conflict of Interest: The authors de- Controlled Stimulation of Muscles. 1400.
clare no competing financial interest. Nature 2012, 485, 368–371. 12. Dvir, T.; Timko, B. P.; Brigham, M. D.;
5. Hochberg, L. R.; Bacher, D.; Jarosiewicz, Naik, S. R.; Karajanagi, S. S.; Levy, O.;
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to thank the Juvenile Diabetes Research der Smagt, P.; et al. Reach and Grasp mensional Cardiac Patches. Nat.
Foundation (JDRF), R.L. would like to ac- by People with Tetraplegia Using a Nanotechnol. 2011, 6, 720–725.
knowledge funding from NIH grants R37- Neurally Controlled Robotic Arm. 13. Aida, T.; Meijer, E. W.; Stupp, S. I.
EB000244, R01-EB006365, and D.S.K. would Nature 2012, 485, 372–375. Functional Supramolecular Poly-
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