Literature Review Structure Title Author’s name Abst.docx
1. Literature Review Structure
Title
Author’s name
Abstract (this can be written last; not necessary for rough draft)
Keywords (a list—not a glossary)
Introduction
Body Headers (these can/should reflect how you assimilate your
sources; see our model
literature reviews)
Conclusion
Acknowledgments
List of References
Neuroscience nanotechnology:
progress, opportunities and challenges
Abstract
What is nanotechnology?
Examples of current work
Applications in basic neuroscience
Applications in clinical neuroscience
Challenges and opportunities
The role of the neuroscientist
Future directions
Acknowledgements
Competing Interests Statement
Databases
Further Information
3. blood–brain barrier (BBB). The third section discusses
some of the unique challenges encountered when apply-
ing nanotechnology to neural cells and the nervous
system, and the tremendous impact this technology
might have on neuroscience research. The fourth sec-
tion attempts to define the roles of neuroscientists in
advancing neuroscience nanotechnology. The final
Departments of
Bioengineering and
Ophthalmology, and the
Neurosciences Program,
University of California,
San Diego, UCSD Jacobs
Retina Center 0946,
9415 Campus Point Drive,
La Jolla, California 92037-
0946, USA.
e-mail: [email protected]
doi:10.1038/nrn1827
Self-assembly
The self-organization of
molecules into supermolecular
structures. Self-assembly is
triggered by specific chemical
or physical variables, such as a
change in temperature or
concentration, and reflects an
energy minimization process.
section speculates on the results that might derive from
current applications of nanotechnology and the types
of applications that might have the earliest impact in
neuroscience.
4. What is nanotechnology?
Nanotechnologies are technologies that use engineered
materials or devices with the smallest functional organi-
zation on the nanometre scale (that is, one billionth of a
metre) in at least one dimension, typically ranging from
1 to ~100 nanometres. This implies that some aspect of
the material or device can be manipulated and controlled
by physical and/or chemical means at nanometre resolu-
tions, which results in functional properties that are
unique to the engineered technology and not shown by
its constituent elements. For example, DNA self-assembly
can yield DNA nanotube supermolecular structures
that form electrically conducting nanowires that have
potential for use in nanoelectronic devices1. In addition,
boron-doped silicon nanowires can function as real-time
ultrahigh sensitive detectors for biological and chemical
factors2: nanowires modified with biotin specifically
and accurately detect picomolar concentrations of
streptavidin. Nanotechnologies are therefore primarily
defined by their functional properties, which determine
how they interact with other disciplines. Although the
chemical and/or physical make up of a nanomaterial or
device is important in the overall technological proc-
ess, it is secondary to their engineering and functional
properties. Considering the two examples described
above, DNA does not have the intrinsic capacity to
function as an electrically conducting nanowire, and
neither boron nor silicon can detect specific chemical
Neuroscience nanotechnology:
progress, opportunities and challenges
Gabriel A. Silva
Abstract | Nanotechnologies exploit materials and devices with
a functional
organization that has been engineered at the nanometre scale.
6. Top-down approaches
(for example, lithography)
a b
Bottom-up technologies
Materials or devices
engineered from constituent
elements such as specific
molecules that are organized
into higher-order functional
structures.
Top-down technologies
Materials or devices that are
engineered from a bulk
material. The various forms of
lithography are examples of
top-down engineering
approaches.
Lithography
The process of producing
patterns in bulk materials.
The most common forms of
lithography are those
associated with the production
of semiconductor integrated
circuits.
species. However, DNA nanowires and boron-doped
silicon have gained these novel functional properties.
These technologies are described by the new functional
outcomes of bringing these components together, not
because they had to contain DNA, or boron or silicon.
7. Other materials or devices can be made using the same
building blocks with different functional or engineered
outcomes, and both electrically conducting nanowires
and high-sensitivity chemical sensors can be produced
using other chemistry and synthetic approaches. In this
functional definition of nanotechnology, it is implicit
that this is not a new area of science per se, and that
the interdisciplinary convergence of basic fields (such
as chemistry, physics, mathematics and biology) and
applied fields (such as materials science and the vari-
ous areas of engineering) contributes to the functional
outcomes of the techno logy. In this framework, nano-
technology can be regarded as an interdisciplinary
pursuit that involves the design, synthesis and character-
ization of nanomaterials and devices that have the types
of property discussed above. In particular, this engineer-
ing definition of nanotechnology is what sets it apart
from chemistry. Chemistry is an integral component
of nanotechnology, but the two are not synonymous, a
point that is a potential source of confusion. Chemistry
involves the manipulation of matter at nanometre scales
resulting in chemical products with specific intrinsic
properties (for example, a defined melting point, pKa or
charge distribution) that affect how they interact with
their environments. As emphasized above, nanotechno-
logies are primarily defined in terms of their extrinsic
engineered functional properties (of which the intrinsic
chemistry could be one of many contributory factors
that define these properties).
From the neuroscientist’s perspective, the most
important aspect of nanotechnologies is the applica-
tion of these technologies to neuroscience questions and
challenges3,4. There are two key types of nano technology
application in neuroscience: ‘platform nanotechnolo-
8. gies’ that can be readily adapted to address neuroscience
questions; and ‘tailored nanotechnologies’ that are speci-
fically designed to resolve a particular neurobiological
issue. This is also the case for other areas of biology and
medicine. Platform nanotechnologies use materials or
devices with unique physical and/or chemical proper-
ties that can potentially have wide-ranging applications
in different fields. These technologies have considerable
promise, and scientists and engineers are constantly
looking for new ways to explore the potential of plat-
form nanotechnologies. Tailored nanotechnologies
begin with a well-defined biological question, and are
developed to specifically address that issue. Owing to
the inherent complexity of biological systems in gen-
eral, and the nervous system in particular, the tailored
approach often results in highly specialized technologies
that are designed to interact with their target systems
in sophisticated and well-defined ways, and so will be
better suited to tackle the particular problem than a
generic platform technology. However, because tailored
nanotechnologies are highly specialized, their broader
application to other biological systems could be limited.
In many cases, the application of particular nanotechno-
logies in neuroscience has been derived from what was
originally a platform technology, and some tailored
technologies can be modified to address other (but
usually related) scientific questions. From a synthesis
standpoint, nanotechno logies can be classified as vari-
ations of bottom-up technologies, such as self-assembly,
or top-down technologies, such as lithographic methods
(BOX 1). Many nanotechnologies combine aspects of
both strategies.
Examples of current work
This section reviews applications of nanotechnology in
basic and clinical neuroscience (TABLE 1). It is organized
9. according to the type of application, and compares dif-
ferent nanotechnology approaches applied to similar or
related neurobiological or physiological objectives. In
general, the discussion provides more breadth than depth
to give the reader a broad sense of ongoing research.
The section is divided into two subsections: appli-
cations of nanotechnology in basic neuroscience; and
applications of nanotechnology in clinical neuroscience.
Applications of nanotechnology in basic neuroscience
include those that investigate molecular, cellular and phys-
iological processes (FIG. 1). This first subsection discusses
three specific areas. First, nanoengineered materials and
Box 1 | Synthetic approaches in nanotechnology
Different approaches used in the synthesis of nanomaterials and
nanodevices can
accommodate solid, liquid, and/or gaseous precursor materials.
In general, most of these
techniques can be classified as bottom-up and top-down
approaches, and strategies that
have elements of both. Bottom-up approaches (panel a) start
with one or more defined
molecular species, which undergo certain processes that result
in a higher-ordered and -
organized structure. Examples of bottom-up approaches include
systems that self-
assemble, a process that is triggered by a local change in a
chemical or physical
condition. Related techniques include templating and
scaffolding methods, such as
biomineralization, which rely on backbone structures to support
and guide the
nucleation and growth of a nanomaterial. Top-down approaches
(panel b) begin with a
11. Quantum
dots
c Engineered materials with
nanoscale physical features
d Patterned neuronal
adhesion and growth
molecules
Cad Fbn PA2 Lam
Cad Fbn PA2 Lam
γ-Aminobutyric acidGABA
BtnAvd
Cadherin Fibronectin Phospholipase A2 Laminin
Avidin Biotin
approaches for promoting neuronal adhesion and growth
to understand the underlying neuro biology of these pro-
cesses or to support other technologies designed to inter-
act with neurons in vivo (for example, coating of recording
or stimulating electrodes)5–10. Second, nanoengineered
materials and approaches for directly interacting, record-
ing and/or stimulating neurons at a molecular level11–13.
Third, imaging applications using nanotechnology tools,
in particular, those that focus on chemically functional-
ized semiconductor quantum dots14–19. Applications of
nanotechnology in clinical neuroscience include research
aimed at limiting and reversing neuropathological disease
states (FIG. 2). This subsection discusses nanotechnology
approaches designed to support and/or promote the
functional regeneration of the nervous system20,21; neuro-
12. protective strategies, in particular those that use fullerene
derivatives22–26; and nanotechnology approaches that
facilitate the delivery of drugs and small molecules across
the BBB27–38.
As with any classification scheme, there might be
a sense of forced categorization when classifying nano-
technologies, as some nanotechnologies can be used
in more than one area. For example, all three of the
basic nanotechnology applications can also contribute
to an understanding of neuropathophysiology; and all
three of the clinical nanotechnology applications can
also increase our understanding of basic molecular and
cellular neurobiology. But, for the most part, basic neuro-
science applications primarily concern themselves with
understanding basic molecular and cellular mechanisms
without necessarily considering their potential clinical
implications, whereas clinical neuroscience applications
are designed to primarily target disease events, and make
use of basic molecular and cellular neurobiology only
when necessary.
Applications in basic neuroscience. Molecular deposition
and lithographic patterning of neuronal-specific mole-
cules with nanometre resolutions5–10 are an extension
of micropatterning approaches39–44. The deposition of
proteins and other molecules that promote and support
neuronal adhesion and growth on surfaces that do not
support these processes enables the geometric selective
patterning and growth of neurons (for example, control-
led neurite extension). This allows the study of cellular
communication and signalling, and provides a test sys-
tem for investigating the effects of drugs and other mol-
ecules. The ability to control this process at nano metre as
Table 1 | Applications of nanotechnologies in neuroscience
13. Nanotechnology Applications Refs
Basic neuroscience
Molecular deposition and
lithographic patterning of
neuronal-specific molecules
with nanometre resolution
Study of cellular communication and
signalling; test systems for drugs and other
molecules
5–10
Atomic force microscopy
(measures molecularly
functionalized surfaces)
Interact, record and/or stimulate neurons
at the molecular level
11–13
Functionalized quantum dots High-resolution spatial and
temporal
imaging; molecular dynamics and tracking
14–19
Clinical neuroscience
Self-assembling peptide
amphiphile nanofibre
networks
14. Neuronal differentiation from progenitor
cells; neural regeneration
20
Derivatives of hydroxyl-
functionalized fullerenes
(fullerenols)
Neuroprotection mediated by limiting the
effects of free radicals following injury
23–26
Poly(ethylene glycol) and
polyethylenimine nanogels;
poly(butylcyanoacrylate)
nanoparticles
Transport of drugs and small molecules
across the blood–brain barrier
27–36
Figure 1 | Applications of nanotechnologies in basic
neuroscience. Nanomaterials and nanodevices that interact with
neurons and glia at the molecular level can be used to influence
and respond to cellular events. In all cases, these
engineered technologies allow controlled interactions at cellular
and subcellular scales. a | Chemically functionalized
fluorescent quantum dot nanocrystals used to visualize ligand–
target interactions. b | Surfaces modified with
neurotransmitter ligands to induce controlled signalling. For
example, GABA (γ-aminobutyric acid) was immobilized, via
an avidin–biotin linkage, to different surfaces to stimulate
16. Nanoscale
scaffold
a Functional nanoparticles
for free radical neuroprotection
b Bioactive nanoscale
scaffold materials for
neural regeneration
Spinal cord
Atomic force microscopy
(AFM). Scanning probe
microscopy that uses a sharp
probe moving over the surface
of a sample to measure
topographic spatial
information.
opposed to micron resolutions enables the investigation
of how neurons respond to anisotropic physical and
chemical cues. Micron-scale patterning can provide a
functional boundary for controlling and influencing
cellular behaviour, but ultimately the neuron detects a
stimulus (or stimuli in the case of multiple signals) that,
because of the (relatively large) micron-scale resolution of
the patterning, is a homogeneous bioactive signal that is
averaged over the entire cell. Nanotechnology approaches
present subcellular stimuli that can vary from one part
of the neuron to another. For example, photolithography
and layer-by-layer self-assembly have been used to pattern
phospholipase A2, which promotes neuronal adhesion,
on a background of poly(diallyldimethylammonium
chloride) (PDDA)8. This approach facilitates nanoscale
17. patterning at resolutions that can yield complex func-
tional architectures that are tailored to the needs of a
particular experiment. Layer-by-layer self-assembly has
also been used on silicon rubber to pattern alternating
laminin and poly-d-lysine or fibronectin/poly-d-lysine
ultrathin layers, which are 3.5–4.4 nm thick, that support
the growth of cerebellar neurons5. These studies suggest
that bioactive ultrathin layers could coat electro des
designed for long-term implants to promote cell adhesion
and limit immune responses. In a different approach,
electrodes coated with nanoporous silicon increased
neurite outgrowth from PC12 cells, which are clonally
derived neuronal precursor cells, compared with uncoated
electrodes, and decreased glial responses, thereby limiting
the insulating effects of the glial scar10. Coating electrodes
with ultrathin bioactive layers might have other advan-
tages, for example, limiting the increase in the thickness
of the electrodes and thereby minimizing local trauma
due to their insertion and resultant cellular responses.
Other research has shown the effects of nanoscale
physical features on neuronal behaviour. Substantia nigra
neurons cultured on silicon dioxide (SiO2) surfaces with
different nanoscale topographies had differential cell
adhesion properties6. Neurons cultured on surfaces
with physical features (that is, surface roughness)
between 20–70 nm adhered and grew better than neurons
cultured on surfaces with features <10 nm or >70 nm.
These neurons also had normal morpho logies and
normal production of tyrosine hydroxylase, a marker of
metabolic activity.
Another emerging area of neuroscience nanotechno-
logy is materials and devices that have been designed to
interact, record and/or stimulate neurons at the mole-
cular level11–13. Recent research has demonstrated the
18. feasibility of functionalizing mica or glass tethered with
the inhibitory neurotransmitter GABA (γ-amino butyric
acid) and its analogue muscimol (5-aminomethyl-
3-hydroxyisoxazole) through biotin–avidin binding
interactions12,13 (FIG. 1). The functional integrity of the
bound version of the neurotransmitter, which in vivo
functions not as a bound ligand but as a diffusible
messenger across the synaptic cleft, was shown electro-
physiologically in vitro by eliciting an agonist response
to cloned GABAA (GABA type A) and GABAC recep-
tors in Xenopus oocytes12. Such sophisticated systems,
although still in the early conceptual and testing phases,
may provide powerful molecule-based platforms for
testing drugs and neural prosthetic devices. At present,
all neural prostheses (including neural retinal prostheses)
rely on micron-scale features and cannot interact with
the nervous system in a controlled way at the molecular
level, which is a significant disadvantage. Other research
is focusing on achieving nanoscale measurements of
cellular responses. Atomic force microscopy (AFM) has
been used to measure local nanometre morphological
responses to micro-electrode array stimulation of neuro-
blastoma cells11. AFM is a technique that, among other
capabilities, allows the measurement of height changes
in the topography of a surface (for example, a living cell
or a synthetic material) with nanometre resolution45,46; in
essence, it is a nanoscale cantilever that measures surface
topologies at the atomic level. This technique can meas-
ure cross-sectional changes in cell height (between 100
and 300 nm), which are produced by biphasic pulses at
a frequency of 1 Hz, thereby providing information on
ultrafine morphological changes to electrical stimuli in
neurons that cannot be achieved by other technologies.
Figure 2 | Applications of nanotechnology in clinical
neuroscience.
20. 2
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Photobleaching
The progressive loss of
fluorescence signal intensity
due to exposure to light. This
can result in a decreased
signal-to-noise ratio.
An area of nanotechnology that holds significant
promise for probing the details of molecular and cellular
processes in neural cells is functionalized semiconduc-
tor quantum dot nanocrystals14–19 (FIG. 1). Quantum dots
are nanometre-sized particles comprising a heavy metal
core of materials such as cadmium–selenium or cad-
mium telluride, with an intermediate unreactive zinc
sulphide shell and an outer coating composed of selective
bio active molecules tailored to a particular application.
The physical nature of quantum dots gives them unique
and highly stable fluorescent optical properties that can
be changed by altering their chemistry and physical size.
Quantum dots can be tagged with fluorescent proteins
of interest using different chemical approaches similar
to fluorophore immunocytochemistry. However, quan-
tum dots have significant advantages compared with
other fluorescent techniques. Quantum dots undergo
minimal photobleaching and, because they have broad
absorption spectra but narrow emission spectra47–50, can
have much higher signal-to-noise ratios, which result
in dramatically improved signal detection. In addition,
quantum dots can be used for single-particle tracking
of target molecules in live cells, such as tracking lig-
22. and–receptor dynamics in the cell membrane51–53 (FIG. 3).
Quantum dot labelling of both fixed and live cells is
well established, and has been used in a wide variety
of cell types — mostly in vitro or in situ54–64, with some
examples in vivo65,66. Despite the growing literature on
the uses of quantum dots in the study of various cell
types, their application in the labelling of neurons14–19
and glia19 has been slower to develop, and care must be
taken to validate labelling methods that are specific for
neural cells, as methods for labelling other cell types are
not necessarily suitable for neural cells19. Recent research
has illustrated the potential of this technology in neu-
roscience. The real-time dynamics of glycine receptors
in spinal neurons have been tracked and analysed using
single-particle tracking over periods of seconds to min-
utes15. These investigators characterized the dynamics of
glycine receptor diffusion, which differed as a function
of the spatial localization of the receptors relative to the
synapse depending on whether they were in synaptic,
perisynaptic or extrasynaptic regions. In another example,
immobilized quantum dots that were conjugated with
β-nerve growth factor (βNGF) were shown to interact
with TrkA receptors in PC12 cells and to regulate their
differentiation into neurons in a controlled way18. This
could provide new tools for studying neuronal signal-
ling processes. Although most applications of quantum
dots in neuroscience have taken place ex vivo, in vivo
microangiography of mouse brains has been achieved
using serum that has been labelled with quantum dots14.
New functionalization and labelling methods of quan-
tum dots have been developed and subsequently tested
using labelled AMPA (α-amino-3-hydroxy-5-methyl-4-
isoxazole propionic acid) neurotransmitter receptors16,
and by measuring the cytotoxicity of hippocampal
neurons17. Although quantum-dot nanotechnology,
when used correctly, has little cytotoxic effects on cells
23. in vitro (so that experimental results are not affected),
their in vivo applications present different challenges
due to the possibility of local and systemic toxicity. To
address these issues, the safety of using quantum dots
with both neural cells and other cell types is an active
area of research67–69.
Applications in clinical neuroscience. Applications of
nanotechnology that are intended to limit and reverse
neurological disorders by promoting neural regenera-
tion and achieving neuroprotection are active areas of
Figure 3 | The quantum dot toolbox. Fluorescent quantum dots
are nanoscale
particles that can be chemically functionalized by attaching a
large variety of
biological molecules to their outer surface (for example,
antibodies, peptides and
trophic factors). This allows specific molecular interactions in
both live and fixed
target cells, which can be visualized at high resolutions by
taking advantage of the
unique optical properties of quantum dots, such as their
prolonged photo-stability
(that is, minimal photobleaching), large excitation absorption
spectra and
extremely narrow emission spectra; specific examples of
applications of quantum
dots in neuroscience can be found in REFS 14–19. a | Primary
rat cortical neurons
labelled with conjugates of quantum dots and anti-β-tubulin III
antibody. β-tubulin
is a neuronal-specific intermediate filament protein and so
serves as a neuronal
marker. b | Primary rat astrocytes labelled with quantum dot–
anti-glial fibrillary
24. acidic protein (GFAP) antibody conjugates. GFAP is a glial
specific intermediate
filament protein. c | One of the main advantages of quantum dot
nanotechnology is
that qualitative observations as well as quantitative data can be
obtained, which
provide detailed molecular and biophysical information about
the biological system
being investigated. For example, by using computational and
morphometric tools,
individual quantum dots can be counted across a sample image
to yield information
on the distribution and number of ligand–target interactions.
This graph shows the
number of quantum dots with a particular intensity. Such
quantitative measures
could be used in measuring the expression level of cellular
markers, such as
β-tubulin in a or GFAP in b, which are conjugated to the
quantum dots. d | Quantum
dots can also be used to carry out single-particle tracking of
ligand–target pairs,
such as tracking the motion of a receptor in a cell membrane.
Illustration of the
trajectory of a field of 55 quantum dots undergoing Brownian
diffusion, with
individual trajectories corresponding to individual quantum
dots. The small size,
photochemistry and bioactivity of functionalized quantum dots
provide an
extensive new toolbox for investigating molecular and cellular
processes in neurons
and glia. Images and data courtesy of the Silva Research Group,
University of
California, San Diego, California, USA.
26. engineered microscale features, and scaffolds derived
from naturally occurring materials such as collagen70–79.
One example of a nanoengineered system derived from
this type of work is PLLA scaffolds with an ultrastructure
consisting of cast PLLA fibres, which have diameters of
50–350 nm and porosity of ~85%20. The scaffolds were
constructed using liquid–liquid phase separation by
dissolving PLLA in tetrahydrofuran (THF) rather than
casting them on glass. When cultured in the scaffolds,
neonatal mouse cerebellar progenitor cells were able to
extend neurites and differentiate into mature neurons. A
fundamentally different approach for the development
of a nanomaterial that promotes and supports neural
regeneration is the self-assembly of nanofibre networks
composed of peptide-amphiphile molecules21 (FIG. 4).
On exposure to physiological ionic conditions, peptide-
amphiphile molecules, which consisted of a hydrophobic
carbon tail and a hydrophilic peptide head group, self-
assembled into a dense network of nanofibres. This
trapped the surrounding water molecules and formed
a weak self-supporting gel at the macroscopic level. The
hydrophilic peptide head groups, which formed the
outside of the fibres, consisted of the bioactive laminin-
derived peptide IKVAV, which promotes neurite sprout-
ing and growth80–83. Encapsulation of neural progenitor
cells from embryonic mouse cortex in the nanofibre net-
works resulted in fast and robust neuronal differentiation
(30% and 50% of neural progenitor cells differentiated
into neurons at 1 and 7 days in vitro, respectively), with
minimal astrocytic differentiation (1% and 5% of neural
progenitor cells differentiated into astrocytes at 1 and 7
days in vitro, respectively). This approach could there-
fore promote neuronal differentiation at an injury site
while potentially limiting the effects of reactive gliosis
and glial scarring, which are ubiquitous neuropathologi-
27. cal disease processes.
Applications of nanotechnologies for neuroprotec-
tion have focused on limiting the damaging effects
of free radicals generated after injury, which is a key
neuropathological process that contributes to CNS
ischaemia, trauma and degenerative disorders84–88.
Fullerenols, which are derivatives of hydroxyl-func-
tionalized fullerenes (molecules composed of regular
arrangements of carbon atoms89–93), have been shown
to have antioxidant properties. They also function as
free radical scavengers, which can lead to a reduction
in the extent of excitotoxicity and apoptosis induced by
glutamate, NMDA (N-methyl-d-aspartate), AMPA and
kainate23–26. Fullerenol-mediated neuroprotection has
been shown in vitro and in vivo. Fullerenol limits exci-
totoxicity and apoptosis of cultured cortical neurons
in vitro, and delays the onset of motor degeneration
in vivo in a mouse model of familial amyotrophic lat-
eral sclerosis. The neuroprotective effect of fullerenols
might be partly mediated by inhibition of glutamate
receptors, as they had no effect on GABAA or taurine
receptors. They also lowered glutamate-induced eleva-
tions in intracellular calcium, which is an important
mechanism of neuronal excitotoxicity23–26.
Another clinically relevant area of intense research
is the design of functionalized nanoparticles that can
be administered systemically and deliver drugs and
small molecules across the BBB27–36. This is a major
clinical objective for the treatment of a wide range
Figure 4 | Example of an engineered nanomaterial for neural
regeneration.
Engineered nanomaterials enable the highly specific induction
of controlled cellular
28. interactions that can promote desired neurobiological effects. a |
Peptide-amphiphile
molecules, which consist of a hydrophilic peptide head group
(green circles) and a
hydrophobic carbon tail (white circles) joined by a peptide
spacer region (yellow
circles), can be coaxed to self-assemble into elongated micelles
to produce a dense
nanofibre matrix99,100. Under physiological conditions, the
self-assembly process traps
the surrounding aqueous environment and macroscopically
produces a self-
supporting gel in which neural progenitor cells and stem cells
can be encapsulated. In
this way, the growth and differentiation of neural progenitor
cells and stem cells can
be controlled. b | An example of a peptide-amphiphile nanogel
on a 12 mm glass
coverslip. c | The surface of the nanofibres consists of laminin-
derived, neuronal-
specific pentapeptides, which are encountered by the
encapsulated cells at high
concentrations, resulting in robust differentiation into neurons
while suppressing
astrocyte differentiation21. The cells are stained for the
neuronal marker β-tubulin III
(green) and the astrocyte marker glial fibrillary acidic protein
(none is present). All
nuclei were stained with a nonspecific nuclear Hoescht stain.
Images courtesy of the
Stupp laboratory, Northwestern University, Evanston, Illinois,
USA.
R E V I E W S
70 | JA N UA RY 2 0 0 6 | VO LU M E 7 w w
30. nism that can be used for shuttling mole cules across the
BBB and then releasing them from the delivery system.
Neuropeptides (such as enkephalins), the NMDA recep-
tor antagonist MRZ 2/576, and the chemotherapeutic
drug doxorubicin have been absorbed onto the surface
of poly(butylcyanoacrylate) nanoparticles coated with
polysorbate 80 (REFS 31,33,34,37,38). The polysorbate
on the surface of the nanoparticles adsorbs apolipo-
protein B and apolipoprotein E from the blood, and the
nanoparticles are taken up by brain capillary endothelial
cells via receptor-mediated endocytosis38. Nanoparticles
that target tumours in the CNS may be a particularly
important application of this technology due to the high
morbidity and mortality associated with often aggres-
sive neoplasms in the physically confined spaces of the
cranium and spinal canal.
Challenges and opportunities
The challenges associated with nanotechnology appli-
cations in neuroscience are numerous, but the impact
it can have on understanding how the nervous system
works, how it fails in disease and how we can intervene
at a molecular level is significant. Ultimately, the chal-
lenges and opportunities presented by nanotechnology
stem from the fact that this technology provides a way
to interact with neural cells at the molecular level,
which has both positive and negative aspects. The abil-
ity to exploit drugs, small molecules, neurotransmitters
and neural developmental factors offers the potential
to tailor technologies to particular applications. For
example, neural developmental factors, such as the
cadherins, laminins and bone morphometric protein
families, as well as their receptors, can be manipulated
in new ways. Nanotechnology offers the capacity to
take advantage of the functional specificity of these
molecules by incorporating them into engineered
31. materials and devices to have highly targeted effects.
The laminins, for example, are large multi-domain
trimeric proteins composed of α, β and γ chains, of
which 12 isoforms are known82,83,94,95. The isoforms con-
tain different bioactive peptide sequences, which have
varying affinities for specific cell types and can induce
different effects. For example, the laminin 1 isoform,
which is the most studied laminin, contains at least 48
different short peptide sequences that promote neuro-
nal adhesion and neurite outgrowth, and some of these
peptides (25 of 48 tested) have such effects on specific
types of neuron82. This degree of molecular specificity,
which is conferred not only by laminins but by many
other signalling molecules that are important in the
development and function of the nervous system, can
be used to design highly selective nanotechnologies.
Indeed, any desired cellular signalling pathway can be
targeted using this approach.
This discussion also suggests the main technical chal-
lenges that are encountered when using nanotechnology
applications in neuroscience: the need for greater spe-
cificity; multiple induced physiological functions; and
minimal side effects. Greater specificity of interactions
with target cells and tissues will result in more signifi-
cant and specific physiological effects, which should also
reduce undesirable and deleterious side effects that are
induced by the technology. Another important chal-
lenge is the requirement for technologies that are able to
multitask, carrying out a diverse set of specific cellular
and physiological functions, such as targeting multiple
receptors or ligands. This is particularly important when
attempting to address multi-dimensional CNS disorders
that are the result of numerous interdependent molecular
and biochemical events (for example, secondary injury
following traumatic brain injury or spinal cord injury).
32. At present, synthetic and engineering processes are not
advanced enough to allow nanotechnologies that have
been designed to interact with the nervous system to
fully meet these criteria.
From a biological perspective, the most significant
successes of nanotechnology applications in neuro-
science will be those that appreciate a detailed under-
standing of neurobiology and take advantage of the
known (and unknown) molecular details. As suggested
above, the main challenge is the ability to design and use
more sophisticated technologies that are able to carry out
highly targeted and specific functions while minimizing
nonspecific interactions. To achieve this, both the design
and engineering aspects of nanotechnology as well as our
understanding of the underlying neurobiology are cru-
cial. This, in turn, will require more interaction between
neuroscientists and physical scientists such as chemists
and materials scientists. This is not a trivial issue as
the scientific language and culture between different
disciplines can vary considerably. This is an increasing
challenge for interdisciplinary science, which requires
people with different training, skills and conceptions
of how science should be conducted coming together
first to understand and agree on a common challenge
or problem, and then to agree on how to address that
issue. The next section discusses further the role of
neuroscientists in the development and application of
nanotechnology.
The above discussion pertains to all applications of
nanotechnology to neuroscience. Applications of nanote-
chnology to the nervous system in vivo present additional
challenges. In particular, the inherent complexity of the
CNS, as well as its difficult and anatomically restrictive
nature, poses a unique set of obstacles. Cellular hetero-
34. are well protected from mechanical and physical injury,
and are immunologically privileged behind the BBB and
blood–retina barrier, which have unique molecular and
cellular environments. Nanotechnologies designed for
in vivo applications must be efficiently delivered with
minimal disruption to these structures before it can carry
out its primary function. This will surely present signifi-
cant technical challenges. Similarly, extreme care must
be taken to understand and avoid potential safety pitfalls,
including both systemic and local side effects associated
with the delivery and primary function of the applied
technology — an issue that is unique to in vivo nanotech-
nology96–98. As mentioned above, investigating the safety
of nanotechnologies is an active and important area of
research67–69. Despite all these challenges, the applica-
tions of nanotechnology both in vivo and ex vivo offer
tremendous opportunities for understanding normal
physiology and for developing therapies.
The role of the neuroscientist
Neuroscientists have a unique role in developing nano-
technologies. Neuroscientists — both researchers and
clinicians — need to identify potential applications of
nanotechnology in neuroscience and neurology to maxi-
mize their impact. Scientists with other specialties can
develop powerful platform technologies and even provide
neuroscience-specific examples, but it is only with direct
input from and in partnership with neuroscientists that
broad neurophysiological and clinical applications can be
properly formulated and addressed. This requires highly
interdisciplinary collaborations with consideration of
the requirements of both parties. Some neuroscientists
develop neuroscience nanotechnologies for their particu-
lar purposes, most likely geared towards specific questions
or objectives for their research. But most neuroscientists
35. find that they lack the expertise and resources needed to
design, synthesize and characterize sophisticated nano-
engineered materials or devices. It would be unrealistic
to assume that we as neuroscientists have knowledge
and skills in these areas that are equivalent to those of
chemists or materials scientists who have devoted their
careers to the synthetic aspects of these technologies.
However, chemists and material scientists do not have the
comprehensive training in neurobiology, neurophysiol-
ogy and neuropathology required to fully appreciate and
exploit the potential of nanotechnology in neuroscience.
Therefore, it is crucial that different disciplines are able
to communicate with each other using a common tech-
nical language, which is not a trivial issue — a nucleus
means different things to a physicist and a cell biologist.
To this end, it is important for neuroscientists who wish
to pursue the development of nanotechnology to educate
themselves across disciplines. To envision new applica-
tions of nanotechnology, it is necessary to understand
what has already been accomplished and what can be
achieved with this technology.
Future directions
Applications of nanotechnology to neuroscience are
already having significant effects, which will continue
in the foreseeable future. Short-term progress has ben-
efited in vitro and ex vivo studies of neural cells, often
supporting or augmenting standard technologies. These
advances contribute to both our basic understanding of
cellular neurobiology and neurophysiology, and to our
understanding and interpretation of neuropathology.
Although the development of nanotechnologies designed
to interact with the nervous system in vivo is slow and
challenging, they will have significant, direct clinical
implications. Nanotechnologies targeted at supporting
cellular or pharmacological therapies or facilitating
36. direct physiological effects in vivo will make significant
contributions to clinical care and prevention. The rea-
son for the tremendous potential that nanotechnology
applications can have in biology and medicine in general
and neuroscience in particular stems from the capacity
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Acknowledgements
This work was supported by the Whitaker Foundation,
Arlingon, Virginia, USA, and the Stein Clinical Research
Institute at the University of California, San Diego, USA.
Quantum dots were kindly provided free of charge by
Quantum Dot Corporation.
Competing interests statement
The author declares no competing financial interests.
DATABASES
The following terms in this article are linked online to:
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
51. AMPA receptors | apolipoprotein B | apolipoprotein E | GABA
A
receptor | NMDA receptors
FURTHER INFORMATION
The National Nanotechnology Initiative:
http://www.nano.gov
Silva’s laboratory: http://www.silva.ucsd.edu
American Academy of Nanomedicine: http://www.
aananomed.org
Nano Science and Technology Institute Nanotechnology to
Neuroscience symposium: http://www.nsti.org/
Nanotech2006/symposia/Nanotech_Neurology.html
Access to this interactive links box is free online.
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61. Introduction:
The topic which I have chosen for my response is sustainable
development in business as it is one of the most important and
emerging topics in the field of business and people are
increasingly becoming conscious about the development in the
sustainable ways. This paper is intended to include a literature
review and response on the topic and it will include some
authentic sources about the topic and these sources will be
compared and contrast with each other.Review:
Sustainable development could be described as the development
by business giving economic benefit but without the depletion
and damaging the natural resources and the environment overall
(Baker, 2006). Past few years of our world has seen a large
scale depletion and deterioration of the natural resources and
the environment due to the egregious economic development
and the revolution of the industrial world all around the globe,
but this has to be stopped now as it, if continued, will lead us to
leaving nothing for our coming generations.
Many experts have their own views regarding the sustainable
development and there are many other concepts such as
corporate footprints and corporate social responsibility that
share some of the tranches of the sustainable development.
There are two schools of thoughts in dealing the sustainable
development and the expenditure on such projects, the first
group of people think that such type of development should be
seen as an expense and a company should only spend to the
extent which they have used from the environment and there
should be nothing added because it is not in the direct interest
of the shareholders and it is against the directors fiduciary duty
of acting the shareholders best interest, as it is in the best
interest of the society or public, not the shareholders. (Gifford,
2004)
The second group has a visions that such expenditure should be
seen as marketing and goodwill enhancing expenditure which is
soon going to be converted to be an asset as such expenditure
62. will direct more customers to the organization and this will add
up to the goodwill and brand of the company as people
nowadays are willing to spend more on a product that has been
produced by a company pursuing greener ways and sustainable
development. This source is also of the opinion that companies
should not only spend on environment what they consumed but
they should act as the responsible citizens of the society and
should add value to the society in every possible way. (Stokke,
1991)Conclusion:
Business previously just surrounded the concepts related to the
money and materialization but recent business studies are
incorporating the environment into the business too as it is
crucial for human life. Both of the source present two different
ideas for the expenditure made on the sustainable development,
although the base of the ideas is the same but the two are
different in outlook as the first one urges a company to just
fulfill what is required while the second one participates into
the detailed sustainable development and considers it as a
responsibility of the companies
References:
Stokke, O. (1991). Sustainable development. London: F. Cass in
association with the European Association of Development
Research and Training Institutes (EADI), Geneva.
Baker, S. (2006). Sustainable development. London: Routledge.
Gifford, C. (2004). Sustainable development. Oxford:
Heinemann Library.
